External preparations for the treatment of dermatoses

ABSTRACT

The first invention provides an external preparation for treating dermatoses comprising vitamin E and squalane, which has an efficacy at least equivalent to that of external preparations containing adrenocortical hormones as the active ingredient. The second invention provides an external preparation for treating dermatoses comprising an adrenocortical hormone, vitamin E and squalane, which is reduced in adrenocortical hormone content as compared with conventional preparations, is also reduced in side effects, and has high clinical efficacy. The third invention provides an external preparation for treating dermatoses comprising a nonsteroidal antiinflammatory agent, vitamin E and squalane and/or squalene, which is reduced in side effects and is highly efficacious. The fourth invention provides an external preparation for treating dermatoses comprising an antihistaminic agent, vitamin E and squalane and/or squalene, which is reduced in side effects and is highly efficacious like the above preparation. The fifth invention provides an external preparation for treating dermatoses comprising vitamin E, squalene and squalane, which is reduced in side effects and is highly efficacious.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.08/750,993 filed Apr. 1, 1997 which application is the national phase ofPCT/JP96/01081 filed Apr. 22, 1996.

TECHNICAL FIELD

The present invention relates to external preparations for the treatmentof dermatoses.

BACKGROUND ART

External preparations containing an adrenocortical hormone have so farbeen used widely in the treatment of dermatoses, in particularintractable dermatoses such as a topic dermatitis and contact dermatitisand it is known that they have high pharmacological effects (GekkanYakuji (Pharmaceuticals Monthly); 26, 8, 55, 1984). Japanese KokaiPublication Sho-62-149620, for instance, discloses an externalpreparation containing an adrenocortical hormone as a principal activecomponent.

However, adrenocortial hormone-containing external preparations maypossibly induce adverse effects at the sites of application, for exampleincreased easy infectivity, skin thinning, vascular wall embrittlementand abnormal activation of the pilosebaceous system and, in addition,the drug substances endermically absorbed may possibly produce systemicadverse effects. Thus, the closest attention should be paid to theirdoses. Therefore, for hydrocortisone acetate, for instance, which is atypical adrenocortical hormone, the Japanese Pharmacopoeia prescribes anupper limit use concentration of about 1% by weight and, fordexamethasone and prednisolone, an upper limit concentration of about0.1 to 0.5% by weight.

On the other hand, external preparations with reduced adverse effectsare also available, for example external preparations containing anonsteroidal antiinflammatory agent and/or an antihistaminic agent.However, as compared with adrenocortical hormone-containing ones, theyare much less effective against such intractable dermatoses as mentionedabove (Shinyaku to Chiryo (New Remedies and Therapy); 25, 298, 41,1984).

As mentioned above, adrenocortical hormones have high pharmacologicaleffects but are disadvantageous in that they have strong side effects.Therefore, it is earnestly desired that preparations with which clinicaleffects comparable to those attained with the conventional preparationscan be produced at lower adrenocortical hormone concentrations bedeveloped. In the state of the art, even if higher clinical effects arerequired, it is impossible to increase their contents to levelsexceeding those currently employed, when their side effects are takeninto consideration.

For solving these problems, Japanese Kokai Publication Sho-61-40210discloses a preparation for treating dermatoses and skin protectionwhich comprises vitamin E and Japanese Kokai Publication Sho-53-136521discloses a preparation for the treatment of vegetating dermatoses whichcontains α-tocopherol. However, these are insufficiently effective inintractable dermatoses possibly due to the low concentration of vitaminE or α-tocopherol in the preparations.

Japanese Kokai Publication Hei-06-179619 discloses an externalpreparation for the treatment of dermatoses which contains vitamin E anda transdermal absorption enhancer. However, when it is administeredcontinuedly for achieving satisfactory therapeutic effects, thetransdermal absorption enhancer may possibly produce skin irritatingeffects.

Furthermore, Japanese Kokai Publication Hei-06-247852 discloses anexternal preparation for the treatment of dermatoses which contains 1 to30% by weight of vitamin E and 1 to 30% by weight of squalene. It isknown that this vitamin E- and squalene-containing external preparationfor treating dermatoses can be widely applied to dermatoses withoutproducing such adverse effects as encountered with thesteroid-containing preparations mentioned above. However, for producinghigher clinical effects, preparations showing still stronger effects aredesired.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, it is an object thereof toprovide an external preparation for the treatment of dermatoses whichhas an efficacy at least equivalent to that of external preparationscontaining an adrenocortical hormone as an active ingredient and whichproduces only reduced adverse effects. In the first aspect thereof, thepresent invention provides an external preparation for the treatment ofdermatoses which comprises vitamin E and squalane.

In a second aspect, it is an object of the present invention to providean external preparation for the treatment of dermatoses in which theadrenocortical hormone content is lower as compared with conventionalpreparations and which can produce high clinical efficacy with reducedside effects. In the second aspect thereof, the present inventionprovides an external preparation for the treatment of dermatoses whichcomprises an adrenocortical hormone, vitamin E and squalane.

In a third aspect, it is an object of the present invention to providean external preparation for the treatment of dermatoses which is highlyefficacious but reduced in side effects. In this third aspect, thepresent invention provides an external preparation for the treatment ofdermatoses which comprises a nonsteroidal antiinflammatory agent,vitamin E and squalane and/or squalene.

In a fourth aspect, it is an object of the present invention to providean external preparation for the treatment of dermatoses which is highlyefficacious but reduced in side effects. In this fourth aspect, thepresent invention provides an external preparation for the treatment ofdermatoses which comprises an antihistaminic agent, vitamin E andsqualane and/or squalene.

In a fifth aspect, it is an object of the present invention to providean external preparation for the treatment of dermatoses which is highlyefficacious but reduced in side effects. In the fifth aspect, thepresent invention provides an external preparation for the treatment ofdermatoses which comprises vitamin E, squalene and squalane.

DETAILED DISCLOSURE OF THE INVENTION

First, the present invention is described in detail in its first aspect.

The external preparation for the treatment of dermatoses according tothe first aspect of the present invention comprises vitamin E andsqualane.

The term “vitamin E” as used herein includes tocopherol (vitamin E) andderivatives thereof and, as examples thereof as listed in the JapanesePharmacopoeia, there may be mentioned dl-α-tocopherol, tocopherolacetate (vitamin E acetate ester), tocopherol succinate (vitamin Esuccinate ester), etc. As extrapharmacopoeial species, there may bementioned, for example, α-tocopherol, β-tocopherol, γ-tocopherol,δ-tocopherol, tocopherol nicotinate (vitamin E nicotinate ester),tocopherol phosphate (vitamin E phosphate ester) and tocopherollinolenate (vitamin E linolenate ester).

The term “squalane” as used herein means a saturated hydrocarbon derivedby reduction from squalene which is a unsaturated hydrocarbon occurringin the liver oil of deep-sea fish, in particular sharks, or in vegetableoils such as olive oil, rice bran oil, wheat germ oil, sesame oil andcotton seed oil. The term also includes synthetic squalane obtained bysynthesis from isoprene.

The above-mentioned vitamin E and squalane both have a curative effecton dermatoses, although the effect is weak, and even when the content ofeither one is low, a synergistic therapeutic effect can be produced byincreasing the content of the other. Even when the contents of both arelow, a distinct therapeutic effect can be produced by using thecomposition continuedly. As for the contents of both in the externalpreparation, therefore, vitamin E is used preferably in a proportion of0.1 to 98% by weight, more preferably exceeding 2% by weight to not morethan 98% by weight, still more preferably 5 to 60% by weight and mostpreferably 10 to 50% by weight, while squalane is used in an amount of 2to 98% by weight, more preferably not less than 2% by weight to lessthan 98% by weight, still more preferably 5 to 60% by weight and mostpreferably 10 to 50% by weight.

The external preparation for the treatment of dermatoses according tothe first aspect of the present invention may further contain atransdermal absorption enhancer in addition to vitamin E and squalane.

Said transdermal absorption enhancer comprises at least one memberselected from the group consisting of N-acylsarcosines (inclusive ofsalts), higher fatty acid esters, dicarboxylic acids (inclusive ofsalts), hydroxycarboxylic esters and fatty acid ethanolamides.

As said N-acylsarcosines, there may be mentioned, for example,N-lauroylsarcosine, N-oleoylsarcosine, N-palmitoylsarcosine,cocoacylsarcosine and the like. As the salts thereof, there may bementioned, for example, the sodium, potassium, magnesium, calcium andaluminum salts of said N-acylsarcosines.

Said higher fatty acid esters are the reaction products of higher fattyacids with alcohols.

Said higher fatty acid contains 10 to 18 carbon atoms; when the numberof carbon atoms is smaller, the product higher fatty acid esters arereadily volatile and when said number is larger, the transdermalabsorption enhancing effect is reduced. Said alcohol should contain 1 to20 carbon atoms; when the number of carbon atoms is greater, thetransdermal absorption enhancing effect is reduced.

As the higher fatty acid having 10 to 18 carbon atoms, there may bementioned, among others, caprylic acid, lauric acid, myristic acid,palmitic acid, stearic acid and like saturated aliphatic monocarboxylicacids; palmitoleic acid, oleic acid, vaccenic acid, linoleic acid,linolenic acid and like unsaturated aliphatic monocarboxylic acids; andsebacic acid and like saturated aliphataic dicarboxylic acids.

As the alcohol having 1 to 20 carbon atoms, there may be mentioned,among others, aliphatic saturated alcohols such as methyl alcohol, ethylalcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutylalcohol, tertiary-butyl alcohol, pentyl alcohol, hexyl alcohol, heptylalcohol, octyl alcohol, capryl alcohol, nonyl alcohol, decyl alcohol,lauryl alcohol, myristyl alcohol, palmityl alcohol and stearyl alcohol.

As said higher fatty acid esters, there may be mentioned, for example,isopropyl myristate, isopropyl palmitate, isopropyl laurate andisopropyl stearate.

The above-mentioned dicarboxylic acids (inclusive of salts) contain 2 to10 carbon atoms; when the number of carbon atoms is greater, thetransdermal absorption enhancing effect is reduced.

As the dicarboxylic acids having 2 to 10 carbon atoms, there may bementioned, among others, saturated aliphatic dicarboxylic acids such asoxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid,pimelic acid and suberic acid; unsaturated aliphatic dicarboxylic acidssuch as fumaric acid and maleic acid; and aromatic dicarboxylic acidssuch as phthalic acid, isophthalic acid and terephthalic acid. As theirsalts, there may be mentioned, for example, the sodium, potassium,magnesium, calcium and aluminum salts of the above-mentioneddicarboxylic acids.

Said hydroxycarboxylic esters are the reaction products ofhydroxycarboxylic acids with alcohols.

The number of carbon atoms contained in said hydroxycarboxylic acidshould be 3 to 6; when smaller, the product hydroxycarboxylic esters arereadily volatile and, when greater, the transdermal absorption enhancingeffect is reduced. The number of carbon atoms in the alcohol mentionedabove should be 1 to 20; when greater, the transdermal absorptionenhancing effect is reduced.

As the hydroxycarboxylic acid having 3 to 6 carbon atoms, there may bementioned, for example, such monocarboxylic acids as lactic acid andglyceric acid and such dicarboxylic acids as malic acid and tartaricacid.

As the alcohol having 1 to 20 carbon atoms, there may be mentioned thesame ones as those to be used in the production of the above-mentionedhigher fatty acid esters.

As specific examples of the hydroxycarboxylic esters, there may bementioned, for example, myristyl lactate and cetyl lactate.

Usable as the above-mentioned fatty acid ethanolamides are fatty acidmonoethanolamides or fatty acid diethanolamides as well as additionproducts of these with alkylene oxide.

As said fatty acid ethanolamides, there may be mentioned, for example,lauric acid monoethanolamide, lauric acid diethanolamide,lauroylmonoethanolamide, palmitic acid monoethanolamide, palmitic aciddiethanolamide, myristic acid monoethanolamide, myristic aciddiethanolamide, lauric acid-myristic acid monoethanolamide, coco fattyacid monoethanolamide, coco fatty acid diethanolamide, polyethoxylatedlauroylmonoethanolamide, polyethoxylated coco fatty acidmonoethanolamide, etc.

Particularly preferred among the transdermal absorption enhancersmentioned above are N-lauroylsarcosine, isopropyl myristate, isopropylpalmitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactateand lauric acid diethanolamide.

The transdermal absorption enhancer preferably includes, but is notlimited to, those mentioned above. Thus, those which are conventionalcan be used.

As regards the content of said transdermal absorption enhancer in theexternal preparation, the transdermal absorption enhancer itself can beused also as a base of the preparation in a certain dosage form and thusit is used preferably in a proportion of 0.1 to 10,000 parts by weight,more preferably 0.1 to 100 parts by weight and still more preferably 0.1to 45 parts by weight, per 100 parts by weight of the sum of vitamin Eand squalane.

The dosage form of the external preparation for the treatment ofdermatoses according to the first aspect of the present invention is notlimited to any particular one but includes, among others, ointments,liniments, lotions and the like prepared by dissolving or dispersing theabove-mentioned ingredients in a base material to give the form ofcream, paste, jelly, gel, emulsion, solution or the like; cataplasms orpoultices and the like prepared by dissolving or dispersing theabove-mentioned ingredients in a base material and spreading the mixtureon a backing material; plasters, tape-form preparations and the likeprepared by dissolving or dispersing the above-mentioned ingredients inan adhesive material and spreading the mixture on a backing material;and so forth. It is also possible to prepare liniments by using vitaminE and squalane alone without using any base material.

Said base material may be any of those pharmaceutically acceptable basematerials which are known for use in preparing ointments, liniments,lotions and the like. Thus, it includes, among others, polymers such assodium alginate, gelatin, corn starch, gum tragacanth, methylcellulose,hydroxyethylcellulose, carboxymethylcellulose, xanthan gum, dextrin,carboxymethylstarch, polyvinyl alcohol, sodium polyacrylate,methoxyethylene-maleic anhydride copolymer, polyvinyl ether,polyvinylpyrrolidone, etc.; fats and oils such as beeswax, olive oil,cacao butter, sesame oil, soybean oil, camellia oil, peanut oil, beeffat, lard, lanolin, etc.; white petrolatum; paraffins; hydrocarbon gelointments (e.g. Plastibase, trademark, available from TaishoPharmaceutical Co.); higher fatty acids such as stearic acid; higheralcohols such as cetyl alcohol, stearyl alcohol, etc.; polyethyleneglycol; and water.

Furthermore, inorganic fillers such as kaolin, bentonite, zinc oxide,titanium oxide, etc., viscosity modifiers, antioxidants, pH adjustingagents, humectants such as glycerol, propylene glycol, etc. and otheradditives may be incorporated as necessary.

Said backing material may suitably be selected depending on the dosageform selected (e.g. capaplasm, plaster, tape-form preparation) but ispreferably impermeable or hardly permeable to the active ingredients andsoft and flexible. Thus, it includes, among others, resin films such ascellulose acetate, ethylcellulose, polyethylene, polypropylene,polyvinyl chloride, vinyl acetate-vinyl chloride copolymers,ethylene-vinyl acetate copolymers, ethylene-vinyl acetate-carbonmonoxide copolymers, ethylene-butyl acrylate-carbon monoxide copolymers,polyvinylidene chloride, polyurethanes, nylons, polyethyleneterephthalate, polybutylene terephthalate, etc., aluminum sheet, wovenfabrics, nonwoven fabrics and the like, and laminated sheets derivedfrom these.

Said adhesive material may be any of those known adhesive materialswhich are pharmaceutically acceptable. Thus, for example, acrylicadhesives, rubber-based adhesives, silicone adhesives, urethane typeadhesives and the like may be mentioned and, among them, acrylicadhesives and rubber-based adhesives are preferred. In the case ofspreading onto the backing material mentioned above, the adhesivematerial may be of the solvent, emulsion or hot-melt type or of anyother appropriate type.

As the acrylic adhesives mentioned above, there may be mentionedpolyalkyl (meth)acrylate-based adhesives prepared by copolymerizingalkyl (meth)acrylates as well as copolymers of an alkyl(meth)acrylate(s) and a polyfunctional monomer(s) copolymerizabletherewith and/or some other vinyl monomer or monomers.

As said alkyl (meth)acrylates, there may be mentioned, for example,2-ethylhexyl (meth)acrylate, dodecyl (meth)acrylate and the like.

As said polyfunctional monomers, there may be mentioned, for example,1,6-hexylene glycol dimethacrylate, tetraethylene glycol diacrylate andthe like. As said other vinyl monomers, there may be mentioned, forexample, N-vinyl-2-pyrrolidone, vinyl acetate and the like.

As said rubber-based adhesives, there may be mentioned adhesivecompositions mainly comprising natural rubber, styrene-isoprene-styreneblock copolymers, styrene-olefin-styrene block copolymers and the like.They generally contain tackifiers such as rosin, hydrogenated rosin,rosin esters, terpene resins, terpene-phenol resins, petroleum resins,coumaron resins, coumaron-indene resins, etc. as added thereto.

The dose of the external preparation for the treatment of dermatosesaccording to the first aspect of the present invention may varydepending on the disease to be treated, the severity of symptoms, thesize of the affected part and other factors but is preferably 0.01 to 10grams daily. Such daily dose is applied to the affected part once or inseveral appropriate divided doses.

As the target diseases to be treated with the external preparation forthe treatment of dermatoses according to the first aspect of the presentinvention, there may be mentioned, for example, rough dry skin, rash,miliaria, sore, chilblains, diaper rash, atopic dermatitis, contactdermatitis, seborrheic dermatitis, lichen Vidal, nummular eczema,housewives' eczema, solar dermatitis, insect bites, pruritus cutaneous,prurigo, drug eruption, toxicoderma, psoriasis, parapsoriasis,pustulosis palmaris et plantaris, lichen planus, lichen nitidus,pityriasis rubra pilaris, pityriasis rosea Gibert, erythema,erythroderma, discoid lupus erythematosus, systemic lupus erythematosus,pemphigus, pemphigoid, Duhring's dermatitis herpetiformis, alopeciaareata, vitiligo vulgaris, sarcoidosis, amyloidosis cutis, keloid,hypertrophic scar, wound, bedsore, skin ulcer, alopecia, hair growingand hair restoration.

The second aspect of the present invention is now described in furtherdetail.

The external preparation for the treatment of dermatoses according tothe second aspect of the present invention comprises an adrenocorticalhormone, vitamin E and squalane.

Said adrenocortical hormone includes hormones secreted from the adrenalcortex and derivatives thereof, such as alclometasone dipropionate,triamcinolone acetonide, fluocinolone acetonide, amcinonide, clobetasolpropionate, clobetasone butyrate, cortisone acetate, diflorasonediacetate, diflucortolone valerate, diflucortolone acetate,difluprednate, dexamethasone, dexamethasone palmitate, dexamethasonepropionate, dexamethasone sodium m-sulfobenzoate, dexamethasone sodiumphosphate, dexamethasone valerate, dexamethasone acetate, dexamethasonesodium sulfate, triamcinolone acetate, paramethasone, paramethasoneacetate, halcinonide, halopredone acetate, hydrocortisone,hydrocortisone sodium succinate, hydrocortisone sodium phosphate,hydrocortisone acetate, hydrocortisone acetate propionate,hydrocortisone butyrate, budesonide, prasterone, fluocinonide,fluorometholone, fluorocortisone acetate, fluoroxycortide, flumethasone,flumethasone pivalate, prednisolone, prednisolone succinate,methylprednisolone succinate, prednisolone butylacetate,methylprednisolone, methylprednisolone sodium succinate, prednisolonesodium phosphate, prednisolone valerate, prednisolone valerate acetate,prednisolone acetate, methylprednisolone acetate, prednisone,beclometasone, beclometasone propionate, betamethasone, betamethasonedipropionate, betamethasone sodium phosphate, betamethasone valerate,betamethasone acetate, etc.

The content of the adrenocortical hormone in the external preparation ispreferably 0.0001 to 2% by weight, more preferably 0.001 to 1% byweight; at lower content levels, the curative effect on dermatoses willbe unsatisfactory, while, at higher levels, side effects will readily beproduced although an increased curative effect may be obtained.

The above-mentioned vitamin E includes those species mentioned inrelation to the first aspect of the present invention.

The vitamin E content in the external preparation is preferably 0.1 to99% by weight, more preferably 0.2 to 80% by weight and still morepreferably 0.5 to 50% by weight; when said content is lower, thetherapeutic effect on dermatoses will be unsatisfactory, while, athigher content levels, the therapeutic effect will no more increase withthe content and, with certain base materials, it becomes difficult tomaintain the dosage form.

The above-mentioned squalane includes those species mentioned inrelation to the first aspect of the present invention.

The squalane content in the external preparation is preferably 0.1 to99% by weight, more preferably 1 to 80% by weight and still morepreferably 5 to 50%; when said content is lower, the therapeutic effecton dermatoses will be unsatisfactory while, at higher content levels,the therapeutic effect will no more increase with the content and, withcertain base materials, it becomes difficult to maintain the dosageform.

A particularly preferred combination of the contents of the respectiveactive ingredients in the external preparation is as follows: 0.001 to0.5% by weight of adrenocortical hormone, 0.5 to 20% by weight ofvitamin E and 10 to 30% by weight of squalane.

The external preparation for the treatment of dermatoses according tothe second aspect of the present invention may further contain at leastone transdermal absorption enhancer selected from the group consistingof N-acylsarcosines (inclusive of salts), higher fatty acid esters whichare reaction products from a higher fatty acid having 10 to 18 carbonatoms and an alcohol having 1 to 20 carbon atoms, dicarboxylic acidshaving 2 to 10 carbon atoms (inclusive of salts), hydroxycarboxylicesters which are reaction products from a hydroxycarboxylic acid having3 to 6 carbon atoms and an alcohol having 1 to 20 carbon atoms, andfatty acid ethanolamides.

Said N-acylsarcosines (inclusive of salts) include, among others, thosespecies mentioned hereinabove in relation to the first aspect of thepresent invention.

Said higher fatty acid esters are reaction products derived from ahigher fatty acid and an alcohol. The number of carbon atoms containedin said higher fatty acid should be 10 to 18; when said number issmaller, the reaction products, higher fatty acid esters will be readilyvolatile, whereas the transdermal absorption enhancing effect will below when said number is larger. The number of carbon atoms contained insaid alcohol should be 1 to 20; when said number is larger, thetransdermal absorption enhancing effect will be low.

The higher fatty acid having 10 to 18 carbon atoms includes, amongothers, those species mentioned above in relation to the first aspect ofthe present invention.

The alcohol having 1 to 20 carbon atoms includes, among others, thosespecies mentioned above in relation to the first aspect of the presentinvention.

Said higher fatty acid esters include, among others, those speciesmentioned above in relation to the first aspect of the presentinvention.

The number of carbon atoms contained in said dicarboxylic acids(inclusive of salts) should be 2 to 10; when said number is greater, thetransdermal absorption enhancing effect will be low.

As examples of the dicarboxylic acids having 2 to 10 carbon atoms(inclusive of salts), there may be mentioned those species mentionedabove in relation to the first aspect of the present invention.

The number of carbon atoms contained in said hydroxycarboxylic acidshould be 3 to 6; when said number is smaller, the producthydroxycarboxylic esters will be readily volatile and when it isgreater, the transdermal absorption enhancing effect will be low. Thenumber of carbon atoms contained in said alcohol should be 1 to 20since, when it is greater, the transdermal absorption enhancing effectwill be low.

As examples of the hydroxycarboxylic acid having 3 to 6 carbon atoms,there may be mentioned those species mentioned above in relation to thefirst aspect of the present invention.

The alcohol having 1 to 20 carbon atoms includes those species to beused in the reaction for producing the above-mentioned higher fatty acidesters.

As examples of said hydroxycarboxylic acid esters, there may bementioned those species mentioned above in relation to the first aspectof the present invention.

Said fatty acid ethanolamides include fatty acid monoethanolamides andfatty acid diethanolamides as well as addition products derivedtherefrom with alkylene oxide.

As examples of such fatty acid ethanolamides, there may be mentionedthose species mentioned above in relation to the first aspect of thepresent invention.

Particularly preferred among the above-mentioned transdermal absorptionenhancers are N-lauroylsarcosine, isopropyl myristate, isopropylpalmitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactateand lauric acid diethanolamide.

While those enhancers mentioned above are preferred, any other knowntransdermal absorption enhancer can also be used.

The content of the above transdermal absorption enhancer in the externalpreparation for the treatment of dermatoses is preferably 0.1 to 25parts by weight, more preferably 1 to 12 parts by weight, per 100 partsby weight of the sum total of the adrenocortical hormone, vitamin E andsqualane; when said content is lower, the transdermal absorptionenhancing effect will be produced only to an unsatisfactory extentwhereas when said content is higher, a skin irritating effect may beproduced or the fluidity will be too high, so that, with certain bases,it will be difficult for the dosage form to hold its shape.

The dosage form of the external preparation for the treatment ofdermatoses according to the second aspect of the present invention isnot limited to any particular one but includes, among others, thosementioned above in relation to the first aspect of the presentinvention. When the composition is prepared from an adrenocorticalhormone, vitamin E and squalane alone without using any base, there isobtained a liniment.

The base may be any of those which are pharmaceutically acceptable.Thus, those which are known as bases for ointments, liniments, lotionsand the like can be used. As examples, there may be mentioned thosementioned above in relation to the first aspect of the presentinvention.

Furthermore, where necessary, inorganic fillers such as kaolin,bentonite, zinc oxide, titanium oxide, etc.; viscosity modifiers;antioxidants; pH adjusting agents; and humectants such as glycerol,propylene glycol, etc. may be added.

The backing material can suitably be selected according to the dosageform (e.g. cataplasm, plaster, tape-form preparation, etc.) but ispreferably one flexible and impermeable or scarcely permeable to theactive ingredients. Examples are those mentioned above in relation tothe first aspect of the present invention.

The adhesive material may be any of those materials which are known tobe pharmaceutically acceptable. Examples are those mentioned above inrelation to the first aspect of the present invention. When thecomposition is to be spread on a support, the adhesive material may beof the solvent, emulsion or hot melt type, for instance.

The dose of the external preparation for the treatment of dermatosesaccording to the second aspect of the present invention may varydepending on the disease to be treated, the severity of symptoms, thesize of the affected part and other factors but preferably is 0.01 to 10g daily. Such daily dose is applied to the affected part all at once orin appropriately divided doses.

The diseases to be treated with the external preparation for thetreatment of dermatoses according to the second aspect of the presentinvention include, among others, those mentioned above in relation tothe first aspect of the present invention.

Now, the third aspect of the present invention is described in furtherdetail.

The external preparation for the treatment of dermatoses according tothe third aspect of the present invention comprises a nonsteroidalantiinflammatory agent, vitamin E and squalane and/or squalene.

Said nonsteroidal antiinflammatory agent includes those ones which areused in known external preparations for dermatoses, such as bufexamac,bendazac, suprofen, ufenamate, ibuprofen piconol, crotamiton,glycyrrhetic acid, etc. Other nonsteroidal antiinflammatory agents suchas aspirin, indomethacin, diclofenac and ibuprofen may also be used.

The content of the nonsteroidal antiinflammatory agent in the externalpreparation is preferably 0.5 to 20% by weight; when said content islower, the curative effect on dermatoses will be unsatisfactory whereasa higher content tends to produce side effects, althouth the curativeeffect will be high. Preferred contents of individual nonsteroidalantiinflammatory agents are, for example, as follows: bufexamac—about 5%by weight; bendazac—about 3% by weight; suprofen—about 1% by weight;ufenamate—about 5% by weight; ibuprofen piconol—about 5% by weight;crotamiton—about 10% by weight; and glycyrrhetic acid—about 2% byweight.

As species of said vitamin E, there may be mentioned, among others,those mentioned above in relation to the first aspect of the presentinvention.

The content of vitamin E in the external preparation is preferably 0.1to 99% by weight, more preferably 0.2 to 80% by weight and still morepreferably 0.5 to 50% by weight; when said content is smaller, thecurative effect on dermatoses will be weak, while a higher content maymake it difficult for the dosage form to hold its shape with certainbase materials.

The term “squalene” as used herein means an unsaturated hydrocarbonoccurring in the liver oil of deep-sea fish, in particular sharks, or invegetable oils such as olive oil, rice bran oil, wheat germ oil, sesameoil, cotton seed oil, etc., and even in human serum cutaneum. Squalaneis a saturated hydrocarbon derived from said squalene by reduction. Italso includes synthetic squalane obtained by synthesis from isoprene.

The content of squalane and/or squalene in the external preparation ispreferably 0.1 to 99% by weight, more preferably 0.1 to 80% by weightand still more preferably 0.5 to 60% by weight; when said content issmaller, the curative effect on dermatoses will be weak while a highercontent may make it difficult for the dosage form to hold its shape withcertain base materials.

A particularly preferred combination of the contents of respectiveactive ingredients in the external preparation is as follows:nonsteroidal antiinflammatory agent—0.5 to 20% by weight; vitamin E—0.5to 50% by weight; and squalane and/or squalene—10 to 50%.

Said vitamin E as well as squalane and/or squalene each individually hasa curative effect on dermatoses, although said effect is weak and, evenwhen the content of either is low, a synergistic therapeutic effect canbe produced in cooperation with the nonsteroidal antiinflammatory agentby increasing the content of the other.

The external preparation for the treatment of dermatoses according tothe third aspect of the present invention may further contain at leastone transdermal absorption enhancer selected from the group consistingof N-acylsarcosines (inclusive of salts), higher fatty acid esters whichare products from a higher fatty acid having 10 to 18 carbon atoms andan alcohol having 1 to 20 carbon atoms, dicarboxylic acids having 2 to10 carbon atoms (inclusive of salts), hydroxycarboxylic acid esterswhich are reaction products from a hydroxycarboxylic acid having 3 to 6carbon atoms and an alcohol having 1 to 20 carbon atoms, and fatty acidethanolamides.

Said N-acylsarcosines (inclusive of salts) include, among others, thosespecies mentioned hereinabove in relation to the first aspect of thepresent invention.

Said higher fatty acid esters are reaction products from a higher fattyacid and an alcohol. The number of carbon atoms contained in said higherfatty acid should be 10 to 18; when said number is smaller, the higherfatty acid esters will be readily volatile whereas the transdermalabsorption enhancing effect will be low when said number is larger. Thenumber of carbon atoms contained in said alcohol should be 1 to 20; whensaid number is larger, the transdermal absorption enhancing effect willbe low.

The higher fatty acid having 10 to 18 carbon atoms includes, amongothers, those species mentioned above in relation to the first aspect ofthe present invention.

The alcohol having 1 to 20 carbon atoms includes, among others, thosespecies mentioned above in relation to the first aspect of the presentinvention.

Said higher fatty acid esters include, among others, those speciesmentioned above in relation to the first aspect of the presentinvention.

The number of carbon atoms contained in said dicarboxylic acids(inclusive of salts) should be 2 to 10; when said number is greater, thetransdermal absorption enhancing effect will be low.

As examples of the dicarboxylic acids having 2 to 10 carbon atoms(inclusive of salts), there may be mentioned those species mentionedabove in relation to the first aspect of the present invention.

Said hydroxycarboxylic acid esters are reaction products from ahydroxycarboxylic acid and an alcohol.

The number of carbon atoms contained in said hydroxycarboxylic acidshould be 3 to 6; when said number is smaller, the producthydroxycarboxylic acid esters will be readily volatile and when it isgreater, the transdermal absorption enhancing effect will be low. Thenumber of carbon atoms contained in said alcohol should be 1 to 20since, when it is greater, the transdermal absorption enhancing effectwill be low.

As examples of the hydroxycarboxylic acid having 3 to 6 carbon atoms,there may be mentioned those species mentioned above in relation to thefirst aspect of the present invention.

The alcohol having 1 to 20 carbon atoms includes those species to beused in the reaction for producing the above-mentioned higher fatty acidesters.

As examples of said hydroxycarboxylic acid esters, there may bementioned those species mentioned above in relation to the first aspectof the present invention.

Said fatty acid ethanolamides include fatty acid monoethanolamides andfatty acid diethanolamides as well as addition products derivedtherefrom with alkylene oxide.

As examples of such fatty acid ethanolamides, there may be mentionedthose species mentioned above in relation to the first aspect of thepresent invention.

Particularly preferred among the above-mentioned transdermal absorptionenhancers are N-lauroylsarcosine, isopropyl myristate, isopropylpalmitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactateand lauric acid diethanolamide.

While those enhancers mentioned above are preferred, any other knowntransdermal absorption enhancer can also be used.

The content of the above transdermal absorption enhancer in the externalpreparation is preferably 0.01 to 250 parts by weight, more preferably0.5 to 100 parts by weight, per 100 parts by weight of the sum total ofthe nonsteroidal antiinflammatory agent, vitamin E and squalane and/orsqualene; when said content is lower, the transdermal absorptionenhancing effect will be produced only to an unsatisfactory extentwhereas when said content is higher, a skin irritating effect may beproduced or the fluidity will be too high, so that, with certain bases,it will be difficult for the dosage form to hold its shape.

The dosage form of the external preparation for the treatment ofdermatoses according to the third aspect of the present invention is notlimited to any particular one but includes, among others, thosementioned above in relation to the first aspect of the presentinvention.

The base may be any of those which are pharmaceutically acceptable.Thus, those which are known as bases for ointments, liniments, lotionsand the like can be used. As examples, there may be mentioned thosementioned above in relation to the first aspect of the presentinvention.

Furthermore, where necessary, such additives as inorganic fillers (e.g.kaolin, bentonite, zinc oxide, titanium oxide, etc.); viscositymodifiers; antioxidants; pH adjusting agents; and humectants such asglycerol, propylene glycol, etc. may be added.

The backing material can suitably be selected according to the dosageform (e.g. cataplasm, plaster, tape-form preparation, etc.) but ispreferably one flexible and impermeable or scarcely permeable to theactive ingredients. Examples are those mentioned above in relation tothe first aspect of the present invention.

The adhesive material may be any of those materials which are known tobe pharmaceutically acceptable. Examples are those mentioned above inrelation to the first aspect of the present invention. When thecomposition is to be spread on a support, the adhesive material may beof the solvent, emulsion or hot melt type, for instance.

The dose of the external preparation for the treatment of dermatosesaccording to the third aspect of the present invention may varydepending on the disease to be treated, the severity of symptoms, thesize of the affected part and other factors but preferably is 0.01 to 10g daily. Such daily dose is applied to the affected part all at once orin appropriately divided doses.

The diseases to be treated with the external preparation for thetreatment of dermatoses according to the third aspect of the presentinvention include, among others, those mentioned above in relation tothe first aspect of the present invention.

Now, the fourth aspect of the present invention is described in furtherdetail.

The external preparation for the treatment of dermatoses according tothe fourth aspect of the present invention comprises an antihistaminicagent, vitamin E and squalane and/or squalene.

Said antihistaminic agent includes, among others, those commonly used inexternal preparations for dermatoses, for example isothipendylhydrochloride, diphenhydramine, diphenhydramine lauryl sulfate, etc.

The content of the antihistaminic agent in the external preparation ispreferably 0.1 to 10% by weight; when said content is lower, thetherapeutic effect on dermatoses will be unsatisfactory whereas a highercontent tends to produce side effects, although the therapeutic effectis higher. Preferred contents of individual antihistaminic agents are,for example, as follows: isothipendyl hydrochloride—about 0.75% byweight; diphenhydramine—about 1% by weight; and diphenhydramine laurylsulfate—about 4% by weight.

As species of said vitamin E, there may be mentioned, among others,those mentioned above in relation to the first aspect of the presentinvention.

The content of vitamin E in the external preparation is preferably 0.1to 99% by weight, more preferably 0.2 to 80% by weight and still morepreferably 0.5 to 50% by weight; when said content is smaller, thecurative effect on dermatoses will be weak while a higher content maymake it difficult for the dosage form to hold its shape with certainbase materials.

Said squalane and/or squalene includes, among others, those speciesmentioned above in relation to the third aspect of the presentinvention.

The content of squalane and/or squalene in the external preparation ispreferably 0.1 to 99% by weight, more preferably 0.1 to 80% by weightand still more preferably 0.5 to 60% by weight; when said content issmaller, the curative effect on dermatoses will be weak while a highercontent may make it difficult for the dosage form to hold its shape withcertain base materials.

A particularly preferred combination of the contents of respectiveactive ingredients in the external preparation is as follows:antihistaminic agent—0.1 to 10% by weight; vitamin E—0.5 to 50% byweight; and squalane and/or squalene—10 to 50% by weight.

Said vitamin E as well as squalane and/or squalene each individually hasa curative effect on dermatoses, although said effect is weak and, evenwhen the content of either is low, a synergistic therapeutic effect canbe produced in cooperation with the antihistaminic agent by increasingthe content of the other.

The external preparation for the treatment of dermatoses according tothe fourth aspect of the present invention may further contain at leastone transdermal absorption enhancer selected from the group consistingof N-acylsarcosines (inclusive of salts), higher fatty acid esters whichare reaction products from a higher fatty acid having 10 to 18 carbonatoms and an alcohol having 1 to 20 carbon atoms, dicarboxylic acidshaving 2 to 10 carbon atoms (inclusive of salts), hydroxycarboxylic acidesters which are reaction products from a hydroxycarboxylic acid having3 to 6 carbon atoms and an alcohol having 1 to 20 carbon atoms, andfatty acid ethanolamides.

Said N-acylsarcosines (inclusive of salts) include, among others, thosespecies mentioned hereinabove in relation to the first aspect of thepresent invention.

Said higher fatty acid esters are reaction products from a higher fattyacid and an alcohol. The number of carbon atoms contained in said higherfatty acid should be 10 to 18; when said number is smaller, the higherfatty acid esters will be readily volatile whereas the transdermalabsorption enhancing effect will be low when said number is larger. Thenumber of carbon atoms contained in said alcohol should be 1 to 20; whensaid number is larger, the transdermal absorption enhancing effect willbe low.

The higher fatty acid having 10 to 18 carbon atoms includes, amongothers, those species mentioned above in relation to the first aspect ofthe present invention.

The alcohol having 1 to 20 carbon atoms includes, among others, thosespecies mentioned above in relation to the first aspect of the presentinvention.

Said higher fatty acid esters include, among others, those speciesmentioned above in relation to the first aspect of the presentinvention.

The number of carbon atoms contained in said dicarboxylic acids(inclusive of salts) should be 2 to 10; when said number is greater, thetransdermal absorption enhancing effect will be low.

As examples of the dicarboxylic acids having 2 to 10 carbon atoms(inclusive of salts), there may be mentioned those species mentionedabove in relation to the first aspect of the present invention.

Said hydroxycarboxylic acid esters are reaction products from ahydroxycarboxylic acid and an alcohol.

The number of carbon atoms contained in said hydroxycarboxylic acidshould be 3 to 6; when said number is smaller, the producthydroxycarboxylic acid esters will be readily volatile and when it isgreater, the transdermal absorption enhancing effect will be low. Thenumber of carbon atoms contained in said alcohol should be 1 to 20since, when it is greater, the transdermal absorption enhancing effectwill be low.

As examples of the hydroxycarboxylic acid having 3 to 6 carbon atoms,there may be mentioned those species mentioned above in relation to thefirst aspect of the present invention.

The alcohol having 1 to 20 carbon atoms includes those species to beused in the reaction for producing the above-mentioned higher fatty acidesters.

As examples of said hydroxycarboxylic acid esters, there may bementioned those species mentioned above in relation to the first aspectof the present invention.

Said fatty acid ethanolamides include fatty acid monoethanolamides andfatty acid diethanolamides as well as addition products derivedtherefrom with alkylene oxide.

As examples of such fatty acid ethanolamides, there may be mentionedthose species mentioned above in relation to the first aspect of thepresent invention.

Particularly preferred among the above-mentioned transdermal absorptionenhancers are N-lauroylsarcosine, isopropyl myristate, isopropylpalmitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactateand lauric acid diethanolamide.

While those enhancers mentioned above are preferred, any other knowntransdermal absorption enhancer can also be used.

The content of the above transdermal absorption enhancer in the externalpreparation is preferably 0.01 to 250 parts by weight, more preferably0.5 to 100 parts by weight, per 100 parts by weight of the sum total ofthe antihistaminic agent, vitamin E and squalane and/or squalene; whensaid content is lower, the transdermal absorption enhancing effect willbe produced only to an unsatisfactory extent whereas when said contentis higher, a skin irritating effect may be produced or the fluidity willbe too high, so that, with certain bases, it will be difficult for thedosage form to hold its shape.

The dosage form of the external preparation for the treatment ofdermatoses according to the fourth aspect of the present invention isnot limited to any particular one but includes, among others, thosementioned above in relation to the first aspect of the presentinvention.

The base may be any of those which are pharmaceutically acceptable.Thus, those which are known as bases for ointments, liniments, lotionsand the like can be used. As examples, there may be mentioned thosementioned above in relation to the first aspect of the presentinvention.

Furthermore, where necessary, such additives as inorganic fillers (e.g.kaolin, bentonite, zinc oxide, titanium oxide, etc.); viscositymodifiers; antioxidants; pH adjusting agents; and humectants such asglycerol, propylene glycol, etc. may be added.

The backing material can suitably be selected according to the dosageform (e.g. cataplasm, plaster, tape-form preparation, etc.) but ispreferably one flexible and impermeable or scarcely permeable to theactive ingredients. Examples are those mentioned above in relation tothe first aspect of the present invention.

The adhesive material may be any of those materials which are known tobe pharmaceutically acceptable. Examples are those mentioned above inrelation to the first aspect of the present invention. When thecomposition is to be spread on a support, the adhesive material may beof the solvent, emulsion or hot melt type, for instance.

The dose of the external preparation for the treatment of dermatosesaccording to the fourth aspect of the present invention may varydepending on the disease to be treated, the severity of symptoms, thesize of the affected part and other factors but preferably is 0.01 to 10g daily. Such daily dose is applied to the affected part all at once orin appropriately divided doses.

The diseases to be treated with the external preparation for thetreatment of dermatoses according to the fourth aspect of the presentinvention include, among others, those mentioned above in relation tothe first aspect of the present invention.

Now, the fifth aspect of the present invention is described in furtherdetail.

The external preparation for the treatment of dermatoses according tothe fifth aspect of the present invention comprises vitamin E, squaleneand squalane.

As species of said vitamin E, there may be mentioned, among others,those mentioned above in relation to the first aspect of the presentinvention.

The content of vitamin E in the external preparation is preferably 0.1to 99.8% by weight, more preferably 2 to 80% by weight and still morepreferably 5 to 60% by weight; when said content is smaller, thecurative effect on dermatoses will be unsatisfactory while, at highercontents, the therapeutic effect will no more increase with the increasein content and, with certain bases, it will be difficult for the dosageform to hold its shape.

Said squalene and/or squalane includes, among others, those speciesmentioned above in relation to the third aspect of the presentinvention.

The content of squalene in the external preparation is preferably 0.1 to99.8% by weight, more preferably 0.1 to 80% by weight and still morepreferably 0.5 to 40% by weight; when said content is smaller, thecurative effect on dermatoses will be weak whereas, at higher contents,the therapeutic effect will no more increase with the increase incontent and, with certain bases, it will be difficult for the dosageform to hold its shape.

The content of squalane in the external preparation is preferably 0.1 to99.8% by weight, more preferably 0.1 to 80% by weight and still morepreferably 0.5 to 60% by weight; when said content is smaller, thecurative effect on dermatoses will be weak whereas, at higher contents,the therapeutic effect will no more increase with the increase incontent and, with certain bases, it will be difficult for the dosageform to hold its shape.

A particularly preferred combination of the contents of respectiveactive ingredients in the external preparation is as follows: vitaminE—10 to 50% by weight; squalene—1.5 to 30% by weight; and squalane—2 to45% by weight.

The external preparation for the treatment of dermatoses according tothe fifth aspect of the present invention may further contain at leastone transdermal absorption enhancer selected from the group consistingof N-acylsarcosines (inclusive of salts), higher fatty acid esters whichare reaction products from a higher fatty acid having 10 to 18 carbonatoms and an alcohol having 1 to 20 carbon atoms, dicarboxylic acidshaving 2 to 10 carbon atoms (inclusive of salts), hydroxycarboxylic acidesters which are reaction products from a hydroxycarboxylic acid having3 to 6 carbon atoms and an alcohol having 1 to 20 carbon atoms, andfatty acid ethanolamides.

Said N-acylsarcosines (inclusive of salts) include, among others, thosespecies mentioned hereinabove in relation to the first aspect of thepresent invention.

Said higher fatty acid esters are reaction products from a higher fattyacid and an alcohol. The number of carbon atoms contained in said higherfatty acid should be 10 to 18; when said number is smaller, the reactionproducts, higher fatty acid esters will be readily volatile whereas thetransdermal absorption enhancing effect will be low when said number islarger. The number of carbon atoms contained in said alcohol should be 1to 20; when said number is larger, the transdermal absorption enhancingeffect will be low.

The higher fatty acid having 10 to 18 carbon atoms includes, amongothers, those species mentioned above in relation to the first aspect ofthe present invention.

The alcohol having 1 to 20 carbon atoms includes, among others, thosespecies mentioned above in relation to the first aspect of the presentinvention.

Said higher fatty acid esters include, among others, those speciesmentioned above in relation to the first aspect of the presentinvention.

The number of carbon atoms contained in said dicarboxylic acids(inclusive of salts) should be 2 to 10; when said number is greater, thetransdermal absorption enhancing effect will be low.

As examples of the dicarboxylic acids having 2 to 10 carbon atoms(inclusive of salts), there may be mentioned those species mentionedabove in relation to the first aspect of the present invention.

Said hydroxycarboxylic acid esters are reaction products from ahydroxycarboxylic acid and an alcohol.

The number of carbon atoms contained in said hydroxycarboxylic acidshould be 3 to 6; when said number is smaller, the producthydroxycarboxylic acid esters will be readily volatile and when it isgreater, the transdermal absorption enhancing effect will be low. Thenumber of carbon atoms contained in said alcohol should be 1 to 20since, when it is greater, the transdermal absorption enhancing effectwill be low.

As examples of the hydroxycarboxylic acid having 3 to 6 carbon atoms,there may be mentioned those species mentioned above in relation to thefirst aspect of the present invention.

The alcohol having 1 to 20 carbon atoms includes those species to beused in the reaction for producing the above-mentioned higher fatty acidesters.

As examples of said hydroxycarboxylic acid esters, there may bementioned those species mentioned above in relation to the first aspectof the present invention.

Said fatty acid ethanolamides include fatty acid monoethanolamides andfatty acid diethanolamides as well as addition products derivedtherefrom with alkylene oxide.

As examples of such fatty acid ethanolamides, there may be mentionedthose species mentioned above in relation to the first aspect of thepresent invention.

Particularly preferred among the above-mentioned transdermal absorptionenhancers are N-lauroylsarcosine, isopropyl myristate, isopropylpalmitate, fumaric acid, maleic acid, myristyl lactate, cetyl lactateand lauric acid diethanolamide.

While those enhancers mentioned above are preferred, any other knowntransdermal absorption enhancer can also be used.

The content of the above transdermal absorption enhancer in the externalpreparation is preferably 0.01 to 250 parts by weight, more preferably0.5 to 100 parts by weight, per 100 parts by weight of the sum total ofvitamin E, squalene and squalane; when said content is lower, thetransdermal absorption enhancing effect will be produced only to anunsatisfactory extent whereas when said content is higher, a skinirritating effect may be produced or the fluidity will be too high, sothat, with certain bases, it will be difficult for the dosage form tohold its shape.

The dosage form of the external preparation for the treatment ofdermatoses according to the fifth aspect of the present invention is notlimited to any particular one but includes, among others, thosementioned above in relation to the first aspect of the presentinvention.

The base may be any of those which are pharmaceutically acceptable.Thus, those which are known as bases for ointments, liniments, lotionsand the like can be used. As examples, there may be mentioned thosementioned above in relation to the first aspect of the presentinvention.

Furthermore, where necessary, such additives as inorganic fillers (e.g.kaolin, bentonite, zinc oxide, titanium oxide, etc.); viscositymodifiers; antioxidants; pH adjusting agents; and humectants such asglycerol, propylene glycol, etc. may be added.

The backing material can suitably be selected according to the dosageform (e.g. cataplasm, plaster, tape-form preparation, etc.) but ispreferably one flexible and impermeable or scarcely permeable to theactive ingredients. Examples are those mentioned above in relation tothe first aspect of the present invention.

The adhesive material may be any of those materials which are known tobe pharmaceutically acceptable. Examples are those mentioned above inrelation to the first aspect of the present invention. When thecomposition is to be spread on a support, the adhesive material may beof the solvent, emulsion or hot melt type, for instance.

The dose of the external preparation for the treatment of dermatosesaccording to the fifth aspect of the present invention may varydepending on the disease to be treated, the severity of symptoms, thesize of the affected part and other factors but preferably is 0.01 to 10g daily. Such daily dose is applied to the affected part all at once orin appropriately divided doses.

The diseases to be treated with the external preparation for thetreatment of dermatoses according to the fifth aspect of the presentinvention include, among others, those mentioned above in relation tothe first aspect of the present invention.

BEST MODES FOR CARRYING OUT THE INVENTION

The following examples are further illustrative of the present inventionbut are by no means limitative of the scope thereof.

EXAMPLES 1 TO 24 AND COMPARATIVE EXAMPLES 1 TO 10

Ointments were prepared by supplying Plastibase (Taisho Pharmaceutical),vitamin E acetate (Wako Pure Chemical Industries), vitamin E nicotinate(Wako Pure Chemical Industries), vitamin E succinate (Sigma Chemical),squalane (Wako Pure Chemical Industries), isopropyl myristate (NacalaiTesque), dexamethasone (Wako Pure Chemical Industries) and prednisolone(Wako Pure Chemical Industries), in amounts specified below in Tables 1to 3, to a mortar, and kneading the mortar contents until the componentsother than Plastibase were dissolved in the latter. In Examples 13, 14,16 and 17, Plastibase was not used, hence the preparations prepared wereliniments.

The thus-obtained ointments and liniments were subjected to tests 1 to 5described below (except for the ointment obtained in Example 18, whichwas not tested). In each test run, five rats were used and the resultswere expressed in terms of mean value.

TEST EXAMPLE 1 Effect on DNCB-induced Primary Skin Irritation(nonallergic dermal inflammatory reaction)

After the frank of 7-week-old Wistar rats was clipped of hairs, 20 μl of2% 2,4-dinitrochlorobenzene (DNCB, Wako Pure ChemicalIndustries)-acetone was applied to the exposed skin area and let drythoroughly to induce nonallergic dermatitis.

Then, 0.1 g samples from the ointments or liniments obtained in theforegoing examples and comparative examples were respectively depositedon a 1 cm (radius) disk of polyethylene sheet and applied against thesite of DNCB-induced dermatitis.

Twenty-four hours after induction of dermatitis, the intensity of localerythema was evaluated using a chromameter (CR-200, Minolta).

In a control run, the ointment base (Plastibase) alone was applied inlieu of the test preparation and erythema intensity measurement wasperformed in the same manner.

From the results of measurement of the erythema intensity (A) at thesite of application of the control and the erythema intensity (B) at thesite of application of the test preparation, the erythema inhibitionpercentage was calculated as follows:

Erythema inhibition (%)=[(A−B)/A]×100

The results thus obtained are shown in Tables 1 to 3.

TEST EXAMPLE 2 Effect on PCA reaction (type I allergic reaction)

(1) Preparation of Rat Anti-DNP-As Serum

Rat anti-DNP-As serum was prepared by the method of Tada and Okumura(Journal of Immunology; 106, 1002, 1971).

Thus, an Ascaris suum (swine roundworm) extract was prepared by themethod of Strejan and Campbell (Journal of Immunology; 98, 893, 1967),and then treated with 2,4-dinitrofenyl sulfate (DNP) by the method ofEisen et al. (Journal of American Chemical Society; 75, 4583, 1953) togive DNP-bound Ascaris suum (DNP-As).

The above DNP-As (1 mg) was dissolved in 1 ml of physiological salinecontaining 1×1010 killed cells of Bordetella pertussis as suspendedtherein and the resulting suspension was administered to female ratsweighing about 200 mg by subcutaneous injection into the dorsum of eachfoot. After 5 days, 0.5 mg of DNP-As was dissolved in 0.5 ml ofphysiological saline and the solution was injected into the right andleft muscles of the back. Eight days after the first injection, bloodwas collected from the abdominal aorta and serum was separated. Thus,rat anti-DNP-As serum was obtained.

(2) PCA Reaction

The above-mentioned rat anti-DNP-As serum was diluted with physiologicalsaline and the dilution was administered to male rats weighing about 120to 200 g by intradermal injection into the back at a dose of 0.05 ml.After 45 hours, 0.1 g of each of the test preparations, the ointmentsand liniments obtained in the above-mentioned examples and comparativeexamples, was applied to the site of injection of anti-DNP-As serum inthe same manner as in Test Example 1.

After 3 further hours, 0.5% Evans' blue solution in physiological salinecontaining the DNP-As antigen was administered by intravenous injectionat a dose of 2.5 ml/kg to thereby induce the PCA reaction.

Thirty minutes later, the animals were sacrificed and the dye that hadleaked out in the area of skin reaction was extracted by the method ofHarada et al. (Journal of Pharmaceutics Pharmacology; 23, 218, 1971),namely by excising the reaction area of the skin, mincing the same andimmersing the same in a mixed solution composed of 0.3% aqueous sodiumsulfate solution and acetone (3:7, v/v) for not less than 48 hours.Then, the dye extracted was assayed by absorbance at 620 nm.

In a control run, the ointment base (Plastibase) alone was applied inlieu of the test preparation, then the same procedure was followed, andthe dye extracted was assayed by absorbance.

From the results of determination of the amount (C) of the dye extractedfrom the site of application of the control and of the amount (D) of thedye extracted from the site of application of each test preparation, thedye-leakage inhibition percentage was calculated as follows:

Dye-leakage inhibition (%)=[(C−D)/C]×100

The results thus obtained are shown in Tables 1 to 3.

TEST EXAMPLE 3 Effect on Delayed Contact Dermal Hypersensitivity (typeIV allergy) Reaction in Rats

After the frank of 5-week-old Wistar rats was clipped of hairs, 20 μl of20% 2,4-dinitrochlorobenzene (DNCB, Wako Pure ChemicalIndustries)-acetone was applied to the exposed skin area and allowed tosit for 2 weeks for sensitization.

After sensitization, the dorsal skin was clipped of hairs and 20 μl of0.5% DNCB-acetone was applied to induce contact dermatitis.

Then, 0.1 g samples from the ointments or liniments obtained in theexamples and comparative examples were respectively applied to the siteof DNCB-induced dermatitis in the same manner as in Test Example 1.

Twenty-four hours after induction of dermatitis, the intensity of localerythema was evaluated using a chromameter (CR-200, Minolta).

In a control run, the ointment base (Plastibase) alone was applied inlieu of the test preparation and erythema intensity measurement wasperformed in the same manner.

From the results of measurement of the erythema intensity (E) at thesite of application of the control and the erythema intensity (F) at thesite of application of the test preparation, the erythema inhibitionpercentage was calculated as follows:

Erythema inhibition (%)=[(E−F)/E]×100

The results thus obtained are shown in Tables 1 to 3.

TEST EXAMPLE 4 Systemic Effect Evaluated in Terms of Body Weight Change

All the rats of the test groups and control group as used in TestExample 3 were weighed before and after testing and the possiblesystemic side effect was evaluated in terms of body weight changes. Theresults obtained are shown in Tables 1 to 3.

TEST EXAMPLE 5 Organoleptic Evaluation of Feel Upon Use

The ointments or liniments obtained in Examples 1 to 17 and 19 to 24were each applied to the skin of five human subjects and evaluated forthe feel upon application thereof according to the criteria mentionedbelow, and the mean value was calculated. The results are shown inTables 1 and 2.

Evaluation criteria:

0: Significant stickiness and flow, no good feel.

1: Stickiness and flow noted.

2: No stickiness or flow, very good feel.

TABLE 1 Composition (weight %) Test Example Vitamin E 1 2 3 4 PlastibaseSpecies Content Squalane IPM Dex Pre (%) (%) (%) (g) 5 Example 1 96 A 22 — — — 25 18 27 −2 2 2 90 A 5 5 — — — 32 20 35 1 2 3 80 A 10 10 — — —39 24 41 1 2 4 60 A 20 20 — — — 68 30 67 0 2 5 50 A 40 10 — — — 72 32 740 2 6 35 A 60 5 — — — 78 35 80 −1 1 7 25 A 70 5 — — — 80 40 85 0 0 8 50A 10 40 — — — 52 27 48 −2 2 9 35 A 5 60 — — — 59 29 52 0 1 10 25 A 5 70— — — 65 34 56 0 0 11 70 A 10 10 10 — — 48 28 50 −1 2 12 50 A 20 20 10 —— 76 32 72 0 2 13 — A 90 10 — — — 82 40 86 0 0

TABLE 2 Composition (weight %) Test Example Vitamin E 1 2 3 4 PlastibaseSpecies Content Squalane IPM Dex Pre (%) (%) (%) (g) 5 Example 14 — A 1090 — — — 67 35 57 0 0 15 20 A 20 20 40 — — 83 38 75 0 1 16 — A 20 20 60— — 86 41 77 1 1 17 — A 10 10 80 — — 62 34 60 1 0 18 97.5 A 0.5 2 — — —— — — — — 19 60 B 20 20 — — — 70 35 71 −1 2 20 50 B 40 10 — — — 73 38 731 2 21 60 C 20 20 — — — 65 27 62 0 2 22 50 C 40 10 — — — 70 30 71 −1 223 50 B 20 20 10 — — 78 36 74 0 2 24 50 C 20 20 10 — — 70 30 68 1 2Control — — — — — — — — — 0 —

TABLE 3 Composition (weight %) Test Example Vitamin E 1 2 3 4 PlastibaseSpecies Content Squalane IPM Dex Pre (%) (%) (%) (g) Comparative 1 80 A— 20 — — — 8 4 7 0 Example 2 60 A — 40 — — — 10 5 9 0 3 80 A 20 — — — —17 7 15 −1 4 60 A 40 — — — — 20 8 17 1 5 70 A — 20 10 — — 11 9 10 0 6 50A — 40 10 — — 14 10 15 −1 7 70 A 20 — 10 — — 20 10 22 0 8 50 A 40 — 10 —— 23 12 24 0 9 99.9 A — — — 0.1 — 49 20 53 −13 10 99.5 A — — — — 0.5 5223 48 −12

In Tables 1 to 3, in the column “Species” below “Vitamin E”, A standsfor vitamin E acetate, B for vitamin E nicotinate, and C for vitamin Esuccinate. In the same tables, IPM stands for isopropyl myristate, Dexfor dexamethasone, and Pre for prednisolone.

The ointments having low vitamin E and low squalane contents as obtainedin Examples 1, 2 and 18 were further tested in the following manner.

TEST EXAMPLE 6 Effect of Repeated Administration on Delayed ContactDermal Hypersensitivity (type IV allergy) Reaction in Rats

After the frank of 5-week-old Wistar rats was clipped of hairs, 20 μl of20% 2,4-dinitrochlorobenzene (DNCB, Wako Pure ChemicalIndustries)-acetone was applied to the exposed skin area and allowed tosit for 2 weeks for sensitization.

After sensitization, the back was clipped of hairs and 0.1 g samplesfrom the ointments obtained in Examples 1, 2 and 18 were respectivelyapplied once daily for 3 days prior to inducing contact dermatitis inthe same manner as in Test Example 1. Three days after commencement ofointment application, 20 μl of 0.5% DNCB-acetone was applied to inducecontact dermatitis.

Then, 0.1 g samples from ointments obtained in Examples 1, 2 and 18 wererespectively applied to the site of DNCB-induced dermatitis in the samemanner as in Test Example 1.

Twenty-four hours after induction of dermatitis, the intensity of localerythema was evaluated using a chromameter (CR-200, Minolta).

In a control run, the ointment base (Plastibase) alone was applied inlieu of the test preparation and erythema intensity measurement wasperformed in the same manner.

From the results of measurement of the erythema intensity (G) at thesite of application of the control and the erythema intensity (H) at thesite of application of the test preparation, erythema inhibitionpercentage was calculated as follows:

Erythema inhibition (%)=[(G−H)/G]×100

The results thus obtained are shown in Table 4.

TABLE 4 Test Composition (weight %) Example Vitamin E 6 PlastibaseSpecies Content Squalene (%) Example 1 96 A 2 2 44 2 90 A 5 5 56 18 97.5 A 0.5 2 38

Furthermore, the ointments obtained in Examples 3 to 5, 8, 11, 12 and 19to 24 and Comparative Examples 9 and 10 were tested in the followingmanner.

In each test run, five rats were used and the results were shown interms of mean value.

TEST EXAMPLE 7 Effect on Type III Allergy Model

(1) Preparation of Rabbit Anti-ovalbumin Serum

Rabbit anti-ovalbumin serum was prepared by the method of Eda et al.(Folia Pharmacologica Japonica; 66, 237, 1970).

Thus, ovalbumin (Sigma) was dissolved in physiological saline to aconcentration of 2 mg/ml. An equivolume mixture (emulsion) of thissolution and Freund's complete adjuvant (Difco) was used as an antigenpreparation and 0.5 ml thereof was injected into the right and leftgluteal muscles of each male rabbit (New Zealand white strain) fourtimes at one-week intervals. Seven days after the last injection bloodwas collected from the carotid artery and serum was separated andrecovered. Thus, rabbit anti-ovalbumin serum was obtained.

(2) Four-hour Heterologous Passive Cutaneous Anaphylaxis Reaction inRats

The above rabbit anti-ovalbumin serum was 4-fold diluted withphysiological saline and 0.05 ml of the dilution was intradermallyinjected into the back of each Wistar strain male rat weighing about 200g. Then, 0.1 g of each of the ointments obtained in the above-mentionedexamples and comparative examples was applied to the rat skin at thesite of application of the antiserum in the same manner as in TestExample 1.

Then, 4 hours after antiserum injection, 0.5% Evans' blue solution inphysiological saline containing 2 mg/ml of ovalbumin was intravenouslyadministered at a dose of 2.5 ml/kg to thereby induce the PCA reaction.

The dye that had leaked out at the site of the thus-inducedintracutaneous reaction was extracted and assayed by the method ofHarada et al. (Journal of Pharmaceutics Pharmacology; 23, 218, 1971).

Thus, 30 minutes after Evans' blue administration, the animals weresacrificed. The skin excised from the reaction area was minced andimmersed in a mixed solution of 0.3% aqueous solution of sodium sulfateand acetone (3:7, v/v) for not less than 48 hours for effectingextraction of the dye that had leaked out. The dye thus extracted wasthen assayed by absorbance at 620 nm.

In a control run, the ointment base (Plastibase) alone was applied inlieu of the test preparation. Thereafter, the same procedure wasfollowed and the dye extracted was assayed by absorbance.

From the results of determination of the amount (I) of the dye extractedfrom the site of application of the control and of the amount (J) of thedye extracted from the site of application of each test preparation, thedye-leakage inhibition percentage was calculated as follows:

Dye-leakage inhibition (%)=[(I−J)/I]×100

The results thus obtained are shown in Tables 5 to 6.

TEST EXAMPLE 8 Effect on Delayed Dermal Hypersensitivity Reaction(tuberculin-induced type IV allergy reaction) in Rats

The method of Kuriyama et al. (Folia Pharmacologica Japonica; 94, 113,1989) was followed.

BCG (Bacillus Calmette-Guerin) (2.5 mg; Nihon BCG) was suspended in 1 mlof physiological saline. The suspension was heat-treated at 121° C. for5 minutes and 0.2 ml thereof was injected into the peritoneal cavity ofeach 9-week-old Wistar rat.

Seven days after BCG injection, 200 μg of purified tuberculin (NihonBCG) was dissolved in 1 ml of physiological saline and two 0.1-mlportions were respectively intradermally injected into two sites on theclipped back of the above rat.

Physiological saline, which was free of purified tuberculin, alone wasalso intradermally injected at another site on the clipped back in thesame manner. Then, 0.1 g of each of the test preparations (ointmentsobtained in the above-mentioned examples and comparative examples)applied in the same manner as in Test Example 1 such that the ointmentcontacted the rat skin at one of the sites of injection of purifiedtuberculin.

As a control, the ointment base (Plastibase) alone was applied, in lieuof the test preparation, to the rat skin at the other tuberculininjection site in the same manner.

Twenty-four hours after said tuberculin injection, the diameter of theresulting erythema was measured and, from the results of measurement ofthe erythema diameter (K) at the control application site and of theerythema diameter (L) at the test preparation application site, theerythema inhibition percentage was calculated as follows:

Erythema inhibition (%)=[(K−L)/K]×100

The results obtained are shown in Tables 5 and 6.

TEST EXAMPLE 9 Effect on Solar Dermatitis (ultraviolet erythema)

The test preparations were examined for effect on ultraviolet-inducederythema by the method of Tsuji et al. (Oyo Yakuri (Pharmacometrics);23, 567, 1982). Thus, the back of guinea pigs weighing 250 to 300 g wasclipped of hairs. The skin of the back was then covered with alight-shielding cloth having three round holes with a diameter of 7 mmand ultraviolet irradiation was carried out from a distance of 20 cm for30 seconds using a 1,000 watt ultraviolet lamp (Toshiba). Each (0.1 g)of the ointments obtained in the above-mentioned examples andcomparative examples was applied as the test preparation to the site ofultraviolet-induced erythema 3 hours prior to irradiation andimmediately after irradiation. Five hours after induction of dermatitis,the intensity of local erythema was evaluated using a chromameter(CR-200, Minolta).

As a control, the ointment base (Plastibase) alone was applied in thesame manner in lieu of the test preparation and thereafter the erythemaintensity was measured following the same procedure.

From the results of measurement of the erythema intensity (M) at thesite of control application site and the erythema intensity (N) at thesite of test preparation application, the erythema inhibition percentagewas calculated as follows:

Erythema inhibition (%)=[(M−N)/M]×100

The results obtained are shown in Tables 5 and 6.

TEST EXAMPLE 10 Effect on Wound Healing

The ointments were evaluated for effect on wound healing by the methodof Sakyo et al. (Oyo Yakuri; 43, 121, 1992).

The back of 5-week-old Wistar rats was shaved of hairs and using asurgical knife, a 30 mm-long incision was made along the median lineunder ether anesthesia. Immediately after incision, the wound wassutured in 3 equispaced positions.

Then, 0.2 g samples from the ointments obtained in the above examplesand comparative examples were respectively spread on gauze (3-ply), 2.5cm×5 cm, and applied to the wounded area and an occulusive dressingusing an elastic adhesive bandage was applied for fixation.

The ointment-coated gauze was exchanged once/daily.

The suture was removed 3 days after commencement of the experiment. Onday 6, the skin covering the whole wounded area was excised from eachrat and 1 cm-wide skin strips parallel to the wound line (2 strips/rat)were prepared. Both ends of each strip were fixed to an NRM-3002D-Lrheometer (Fudoh) and the tension force (g/cm) required for cutting thestrip at the wound site was measured. The mean measured value for twostrips was taken as the tension value for one sample.

As a control, the ointment base (Plastibase) alone was applied in thesame manner in lieu of the test preparation and thereafter tensionmeasurements were carried out following the same procedure.

The results obtained are shown in Tables 5 and 6.

TABLE 5 Composition (weight %) Test Example Vitamin E 7 8 9 10Plastibase Species Content Squalane IPM Dex Pre (%) (%) (%) (g/cm)Example 3 80 A 10 10 — — — 19 16 30 230 4 60 A 20 20 — — — 25 21 37 2485 50 A 40 10 — — — 30 29 43 263 8 50 A 10 40 — — — 29 27 39 251 11 70 A10 10 10 — — 23 21 36 246 12 50 A 20 20 10 — — 30 28 42 261

TABLE 6 Composition (weight %) Test Example Vitamin E 7 8 9 10Plastibase Species Content Squalane IPM Dex Pre (%) (%) (%) (g/cm)Example 19 60 B 20 20 — — — 30 20 36 247 20 50 B 40 10 — — — 35 28 45264 21 60 C 20 20 — — — 23 18 35 240 22 50 C 40 10 — — — 28 25 39 255 2350 B 20 20 10 — — 35 29 43 263 24 50 C 20 20 10 — — 28 26 40 258Comparative 9 99.9 — — — 0.1 — 28 23 17 — Example 10 99.5 — — — — 0.5 2520 13 — Control — — — — — — — — — 175

When tested in the above manner, the external preparation for thetreatment of dermatoses according to the first aspect of the presentinvention showed effects equivalent to those of external preparationscontaining an absorption enhancer or adrenocortical hormone and, unlikethe adrenocortical hormone-containing external preparations, did notshow any body weight loss due to side effects.

As compared with the single use of vitamin E or squalane, the combineduse of both produced remarkable effects.

EXAMPLES 25 TO 47

Ointments were prepared by supplying white petrolatum (MaruishiPharmaceutical), vitamin E acetate (Wako Pure Chemical Industries),vitamin E nicotinate (Wako Pure Chemical Industries), vitamin Esuccinate (Sigma), squalane (Wako Pure Chemical Industries),N-lauroylsarcosine (Nacalai Tesque), fumaric acid (Nacalai Tesque),cetyl lactate (Van-Dyk) and isopropyl myristate (Nacalai Tesque), inamounts specified below in Table 7, to a mortar, and kneading the mortarcontents until the components other than white petrolatum were dissolvedin the latter.

TABLE 7 Composition (weight %) White Vitamin E Fumaric Cetyl petrolatumSpecies Content Squalane LS acid lactate IPM Example 25 79 A 10 10 1 — —— 26 59 A 20 20 1 — — — 27 19 A 40 40 1 — — — 28 79 A 10 10 — 1 — — 2959 A 20 20 — 1 — — 30 19 A 40 40 — 1 — — 31 79 A 10 10 — — 1 — 32 59 A20 20 — — 1 — 33 19 A 40 40 — — 1 — 34 70 A 10 10 — — — 10 35 50 A 20 20— — — 10 36 10 A 40 40 — — — 10 37 80 A 10 10 — — — — 38 60 A 20 20 — —— — 39 20 A 40 40 — — — — 40 59 B 20 20 1 — — — 41 59 B 20 20 — 1 — — 4259 B 20 20 — — 1 — 43 50 B 20 20 — — — 10 44 59 C 20 20 1 — — — 45 59 C20 20 — 1 — — 46 59 C 20 20 — — 1 — 47 50 C 20 20 — — — 10

In Table 7, in the column “Species” under “Vitamin E”, A stands forvitamin E acetate, B for vitamin E nicotinate, and C for vitamin Esuccinate. In the same table, IPM stands for isopropyl myristate, and LSfor N-lauroylsarcosine.

EXAMPLE 48

Vitamin E acetate (40% by weight; Wako Pure Chemical Industries), 40% byweight of squalane (Wako Pure Chemical Industries) and 20% by weight ofolive oil were supplied to a beaker and the contents were stirred untilhomogeneous dissolution of the whole, to give a liniment.

EXAMPLE 49

Vitamin E acetate (20% by weight; Wako Pure Chemical Industries), 20% byweight of squalane (Wako Pure Chemical Industries) and 60% by weight ofolive oil were supplied to a beaker and the contents were stirred untilhomogeneous dissolution of the whole, to give a liniment.

EXAMPLE 50

Vitamin E nicotinate (40% by weight; Wako Pure Chemical Industries), 40%by weight of squalane (Wako Pure Chemical Industries) and 20% by weightof olive oil were supplied to a beaker and the contents were stirreduntil homogeneous dissolution of the whole, to give a liniment.

EXAMPLE 51

Vitamin E succinate (40% by weight; Sigma), 40% by weight of squalane(Wako Pure Chemical Industries) and 20% by weight of olive oil weresupplied to a beaker and the contents were stirred until homogeneousdissolution of the whole, to give a liniment.

EXAMPLE 52

[Synthesis of acrylic adhesive]

A separable flask equipped with a stirrer and a condenser was chargedwith 301.1 weight parts of 2-ethylhexyl methacrylate, 34.9 weight partsof 2-ethylhexyl acrylate, 48.3 weight parts of dodecyl methacrylate,0.0384 weight part of 1,6-hexaneglycol dimethacrylate and 256.0 weightparts of ethyl acetate, and the mixture was heated to 70° C. withstirring and nitrogen substitution.

A solution of 2.0 weight parts of lauroyl peroxide in 10.0 weight partsof cyclohexane was divided into 10 aliquots. One aliquot was added tothe separable flask to thereby initiate the polymerization. Starting at5 hours after initiation of the polymerization, the remaining 9 aliquotswere added one by one at 1-hour intervals. After completion of theaddition, the reaction was further continued for 19 hours. For viscosityadjustment, five 27 weight part portions of ethyl acetate were added oneby one at 5-hour intervals after initiation of the reaction.

After completion of the reaction, the reaction mixture was cooled andethyl acetate was further added to give an adhesive solution with asolid content of 50% by weight.

[Production of tape-form preparation]

The above adhesive solution (120 weight parts), 20 weight parts ofvitamin E acetate (Wako Pure Chemical Industries) and 20 weight parts ofsqualane (Wako Pure Chemical Industries) were supplied to adissolver-type high-speed mixer and homogeneously blended to give amixed solution.

The thus-obtained mixed solution was applied to a silicone-treatedpolyethylene terephthalate film (38 μm thick) and then dried at 60° C.for 30 minutes to give a 80-μm-thick adhesive layer.

The above adhesive layer was then transferred onto the ethylene-vinylacetate copolymer layer of a 34 μm thick polyethyleneterephthalate/ethylene-vinyl acetate copolymer laminate film, to give atape-form preparation.

EXAMPLE 53

A tape-form preparation was produced by following the procedure ofExample 52 except that the adhesive solution was used in an amount of180 weight parts, vitamin E acetate in an amount of 5 weight parts andsqualane in an amount of 5 weight parts.

EXAMPLE 54

A tape-form preparation was produced by following the procedure ofExample 52 except that the adhesive solution was used in an amount of120 weight parts, 20 weight parts of vitamin E nicotinate (Wako PureChemical Industries) was used in lieu of 20 weight parts of vitamin Eacetate, and squalane was used in an amount of 20 weight parts.

EXAMPLE 55

A tape-form preparation was produced by following the procedure ofExample 52 except that the adhesive solution was used in an amount of120 weight parts, 20 weight parts of vitamin E succinate (Sigma) wasused in lieu of 20 weight parts of vitamin E acetate, and squalane wasused in an amount of 20 weight parts.

EXAMPLES 56 TO 79 AND COMPARATIVE EXAMPLES 11 TO 20

Ointments were prepared by supplying Plastibase (Taisho Pharmaceutical),dexamethasone (Wako Pure Chemical Industries), prednisolone (Wako PureChemical Industries), triamcinolone acetonide (Wako Pure ChemicalIndustries), vitamin E acetate (Wako Pure Chemical Industries) andsqualane (Wako Pure Chemical Industries), in amounts specified below inTables 8 and 9, to a mortar, and kneading the mortar contents until thecomponents other than Plastibase were dissolved in the latter.

In Tables 8 and 9, Tac stands for triamcinolone acetonide.

TABLE 8 Composition (weight %) Plasti- Dexa- Pred- base methasonenisolone Tac Vitamin E Squalane Example 56 84.400 0.1 — — 0.5 15 5764.900 0.1 — — 20 15 58 84.490 0.01 — — 0.5 15 59 64.990 0.01 — — 20 1560 84.499 0.001 — — 0.5 15 61 64.999 0.001 — — 20 15 62 69.499 0.001 — —0.5 30 63 49.999 0.001 — — 20 30 64 84.000 — 0.5 — 0.5 15 65 64.500 —0.5 — 20 15 66 84.450 — 0.05 — 0.5 15 67 64.950 — 0.05 — 20 15 68 84.490— 0.01 — 0.5 15 69 64.990 — 0.01 — 20 15 70 84.495 — 0.005 — 0.5 15 7164.995 — 0.005 — 20 15 72 69.495 — 0.005 — 0.5 30 73 49.995 — 0.005 — 2030 74 84.400 — — 0.1 0.5 15 75 64.900 — — 0.1 20 15 76 84.490 — — 0.010.5 15 77 64.990 — — 0.01 20 15 78 84.499 — — 0.001 0.5 15 79 64.999 — —0.001 20 15

TABLE 9 Composition (weight %) Plasti- Dexa- Pred- Vitamin basemethasone nisolone Tac E Squalane Comparative Example 11 99.900 0.1 — —— — 12 99.990 0.01 — — — — 13 99.999 0.001 — — — — 14 99.500 — 0.5 — — —15 99.950 — 0.05 — — — 16 99.990 — 0.01 — — — 17 99.995 — 0.005 — — — 1899.900 — — 0.1 — — 19 99.990 — — 0.01 — — 20 99.999 — — 0.001 — —

The thus-obtained ointments were tested as in Test Examples 1 to 5, 7and 9 and further tested as described below in Test Example 11. In TestExamples 1 to 4, 7 and 11, each ointment was evaluated using 5 rats andthe results were expressed in terms of mean value. In Test Example 9, 5guinea pigs were used for each ointment and the results were expressedin terms of mean value. The results obtained are shown in Tables 10 and11.

TEST EXAMPLE 11 Effect on Delayed Dermal Hypersensitivity Reaction(tuberculin reaction) in Rats

The method of Kuriyama et al. (Folia Pharmacologica Japonica; 94, 113,1989) was used.

Thus, 2.5 mg of BCG (Bacillus Calmette-Geurin; Nihon BCG) was suspendedin 1 ml of physiological saline, the suspension was heat-treated at 121°C. for 5 minutes and a 0.2-ml portion thereof was injected into theperitoneal cavity of each 9-week-old Wistar rat.

Seven days after BCG injection, 0.1 ml of a solution prepared bydissolving 200 μg of purified tuberculin (Nihon BCG) in 1 ml ofphysiological saline was intradermally injected into two sites on theclipped back the above rat. Physiological saline, which was free ofpurified tuberculin, alone was intradermally injected at another site onthe clipped back in the same manner. Then, 0.1 g of each of the testpreparations obtained in the above-mentioned examples and comparativeexamples was applied in the same manner as in Test Example 1 so that theointment came into contact with one of the purified tuberculin injectionsites on the rat skin.

As a control, the ointment base (Plastibase) alone was applied in thesame manner to the other tuberculin injection site on the rat skin.

Twenty-four hours after tuberculin injection, the color tone of theresulting erythema was measured using a chromameter. From the results ofmeasurement of the color difference value (K) for the erythema at thecontrol application site and of the color difference value (L) for theerythema at the test preparation application site, the erythemainhibition percentage was calculated as follows:

Erythema inhibition (%)=[(K−L)/K]×100

The results obtained are shown in Tables 10 and 11.

TABLE 10 Test Example 1 2 3 4 7 9 11 (%) (%) (%) (g) 5 (%) (%) (%)Example 56 65.4 50.9 64.1 −5 2 — 31.6 42.8 57 70.1 61.2 68.4 −4 2 — 40.350.3 58 37.5 22.8 42.0 −1 2 35.6 — 23.4 59 47.3 31.2 52.1 0 2 44.8 —30.9 60 15.3 5.9 10.4 1 2 — — 9.6 61 27.1 15.4 24.1 2 2 — — 14.8 62 18.27.9 13.2 2 2 — — 12.1 63 30.9 21.4 27.3 2 0 — — 18.8 64 65.8 49.8 64.6−6 2 — 31.0 44.1 65 69.4 60.3 68.5 −6 2 — 39.2 48.3 66 37.6 30.4 37.1 −42 34.1 — 20.6 67 49.8 36.8 47.1 −4 2 42.9 — 30.0 68 25.1 21.8 23.1 −2 2— — 13.4 69 38.3 30.4 39.6 −1 2 — — 20.6 70 14.9 5.7 9.8 1 2 — — 7.9 7126.9 14.6 23.6 1 2 — — 14.2 72 17.8 7.0 12.3 2 2 — — 11.0 73 30.1 19.826.1 2 0 — — 17.4 74 64.2 50.3 63.9 −5 2 — 31.4 43.2 75 70.3 60.8 68.3−5 2 — 40.0 51.0 76 37.8 22.4 42.3 −3 2 35.2 — 23.6 77 47.0 31.1 51.6 −22 44.5 — 29.8 78 15.4 5.4 10.3 2 2 — — 9.4 79 26.9 15.3 24.3 2 2 — —14.5 Control — — — 0 — — — —

TABLE 11 Text Example 1 2 3 4 7 9 11 (%) (%) (%) (g) 5 (%) (%) (%)Comparative 11 50.6 42.8 53.1 −5 2 50.1 29.2 39.1 Example 12 26.3 21.127.4 −4 2 30.1 5.3 18.7 13 1.2 0.8 0.7 0 2 — — 0.3 14 52.1 43.6 55.2 −62 48.2 27.3 41.0 15 27.2 22.1 26.4 −4 2 28.5 4.0 16.8 16 9.4 7.6 8.6 −22 — — 6.3 17 0.8 0.5 0.5 0 2 — — 0.2 18 51.8 42.7 54.8 −5 2 49.8 28.540.8 19 23.1 20.0 26.1 −3 2 29.5 5.1 13.1 20 0.7 0.6 0.8 0 2 — — 0.2

The results shown in Tables 10 and 11 indicate that the externalpreparation for the treatment of dermatoses according to the secondaspect of the present invention have high curative effects on dermatosesas compared with the conventional adrenocortical hormone-containingexternal preparations. Thus, it was proved that the second aspect of thepresent invention provides highly safe external preparations fordermatoses which are widely efficacious against dermatoses even when theadrenocortical hormone content is low.

EXAMPLES 80 TO 109

Ointments were prepared by supplying Plastibase (Taisho Pharmaceutical),white petrolatum (maruishi Pharmaceutical), amcinonide (Sigma),diflucortolone valerate (Sigma), dexamethasone (Wako Pure ChemicalIndustries), dexamethasone acetate (Sigma), halcinonide (Sigma),hydrocortisone acetate (Wako Pure Chemical Industries), fluocinonide(Sigma), flumethasone pivalate (Sigma), prednisolone (Wako Pure ChemicalIndustries), betamethasone dipropionate (Wako Pure Chemical Industries),betamethasone valerate (Wako Pure Chemical Industries), vitamin Eacetate (Wako Pure Chemical Industries), squalane (Wako Pure ChemicalIndustries), isopropyl myristate (Nacalai Tesque) and N-lauroylsarcosine(Nacalai Tesque), in amounts specified below in Tables 12 and 13, to amortar, and kneading the mortar contents until the components other thanthe base (Plastibase or white petrolatum) were dissolved in the latter.

In Tables 12 and 13, in the column “Species” below “Base”, A stands forPlastibase and B for white petrolatum. In the column “Species” below“Adrenocortical hormone”, F stands for amcinonide, G for diflucortolonevalerate, H for dexamethasone, I for dexamethasone acetate, J forhalcinonide, K for hydrocortisone acetate, L for fluocinonide, M forflumethasone pivalate, N for prednisolone, O for betamethasonedipropionate and P for betamethasone valerate. In the column “IPM”, IPMstands for isopropyl myristate and, in the column “LS”, LS stands forN-lauroylsarcosine.

TABLE 12 Composition (weight %) Adrenocortical Base hormone SpeciesContent Species Content Vitamin E Squalane IPM LS Example 80 A 84.498 F0.002 0.5 15 — — 81 A 69.999 F 0.001 10 20 — — 82 A 79.998 G 0.002 5 15— — 83 A 54.998 G 0.002 15 30 — — 84 A 84.996 H 0.004 5 10 — — 85 A69.999 H 0.001 20 10 — — 86 A 88.499 H 0.001 0.5 10 1 — 87 A 68.999 H0.001 20 10 1 — 88 A 89.399 H 0.001 0.5 10 — 0.1 89 A 69.899 H 0.001 2010 — 0.1 90 A 79.990 I 0.010 5 15 — — 91 A 24.999 I 0.001 30 45 — — 92 A79.990 J 0.010 5 15 — — 93 A 54.999 J 0.001 30 15 — — 94 B 68.500 K1.000 0.5 30 — — 95 B 49.900 K 0.100 20 30 — — 96 B 54.998 L 0.002 15 30— — 97 B 69.999 L 0.001 15 15 — — 98 B 83.999 M 0.001 1 15 — — 99 B44.999 M 0.001 40 15 — — 100 B 84.490 N 0.010 0.5 15 — — 101 B 64.990 N0.010 20 15 — —

TABLE 13 Composition (weight %) Adrenocortical Base hormone SpeciesContent Species Content Vitamin E Squalane IPM LS Example 102 B 83.499 N0.001 0.5 15 1 — 103 B 63.999 N 0.001 20 15 1 — 104 B 84.399 N 0.001 0.515 — 0.1 105 B 64.899 N 0.001 20 15 — 0.1 106 B 83.497 O 0.003 1.5 15 —— 107 B 64.999 O 0.001 5 30 — — 108 B 83.498 P 0.002 1.5 15 — — 109 B69.999 P 0.001 15 15 — — 110 C 84.498 H 0.002 0.5 15 — — 111 D 49.999 H0.001 20 30 — — 112 C 54.490 I 0.01 0.5 45 — — 113 D 29.995 I 0.005 2050 — — 114 C 84.000 K 0.5 0.5 15 — — 115 D 49.900 K 0.1 20 30 — — 116 C83.490 N 0.01 1.5 15 — — 117 E 68.480 N 0.02 1.5 30 — — 118 C 69.995 P0.005 15 15 — — 119 E 54.999 P 0.001 30 15 — —

EXAMPLES 110 TO 146

Liniments were prepared by supplying olive oil (MaruishiPharmaceutical), sesame oil (Maruishi Pharmaceutical), peanut oil(Maruishi Pharmaceutical), dexamethasone (Wako Pure ChemicalIndustries), dexamethasone acetate (Sigma), hydrocortisone acetate (WakoPure Chemical Industries), prednisolone (Wako Pure Chemical Industries),betamethasone valerate (Wako Pure Chemical Industries), vitamin Eacetate (Wako Pure Chemical Industries) and squalane (Wako Pure ChemicalIndustries), in amounts specified below in Table 13 (shown above) andTable 14, to a mortar, and stirring the mortar contents until the base(olive oil, sesame oil or peanut oil) and other additives werehomogeneously mixed up.

In Tables 13 and 14, in the column “Species” below “Base”, C stands forolive oil, D for sesame oil and E for peanut oil. In the column“Species” below “Adrenocortical hormone”, H, I, K, N and P are the sameas in Tables 12 and 13.

TABLE 14 Composition (weight %) Adrenocortical hormone Base SpeciesContent Vitamin E Squalane IPM LS Example 120 — N 0.01 0.5 99.49 — — 121— N 0.01 5 94.99 — — 122 — N 0.01 15 84.99 — — 123 — N 0.01 30 69.99 — —124 — N 0.01 45 54.99 — — 125 — N 0.01 60 39.99 — — 126 — N 0.01 7524.99 — — 127 — N 0.01 90 9.99 — — 128 — N 0.01 98 1.99 — — 129 — I0.005 0.5 99.495 — — 130 — I 0.005 5 94.995 — — 131 — I 0.005 15 84.995— — 132 — I 0.005 30 69.995 — — 133 — I 0.005 45 54.995 — — 134 — I0.005 60 39.995 — — 135 — I 0.005 75 24.995 — — 136 — I 0.005 90 9.995 —— 137 — I 0.005 98 1.995 — — 138 — P 0.001 0.5 99.499 — — 139 — P 0.0015 94.999 — — 140 — P 0.001 15 84.999 — — 141 — P 0.001 30 69.999 — — 142— P 0.001 45 54.999 — — 143 — P 0.001 60 39.999 — — 144 — P 0.001 7524.999 — — 145 — P 0.001 90 9.999 — — 146 — P 0.001 98 1.999 — —

EXAMPLE 147

[Synthesis of acrylic adhesive]

A separable flask equipped with a stirrer and a condenser was chargedwith 301.1 weight parts of 2-ethylhexyl methacrylate, 34.9 weight partsof 2-ethylhexyl acrylate, 48.3 weight parts of dodecyl methacrylate,0.0384 weight part of 1,6-hexaneglycol dimethacrylate and 256.0 weightparts of ethyl acetate, and the flask contents were heated to 70° C.with stirring and nitrogen substitution.

A solution of 2.0 weight parts of lauroyl peroxide in 10.0 weight partsof cyclohexane was divided into 10 aliquots. One aliquot was added tothe separable flask to thereby initiate the polymerization. Starting at5 hours after initiation of the polymerization, the remaining 9 aliquotswere added one by one at 1-hour intervals. After completion of theaddition, the reaction was further carried out for 19 hours. Forviscosity adjustment, five 27 weight part portions of ethyl acetate wereadded one by one at 5-hour intervals after initiation of the reaction.

After completion of the reaction, the reaction mixture was cooled andethyl acetate was further added to give an adhesive solution with asolid content of 50% by weight.

[Production of tape-form preparation]

The above adhesive solution (168.98 weight parts), 0.01 weight part ofprednisolone (Wako Pure Chemical Industries), 0.5 weight part of vitaminE acetate (Wako Pure Chemical Industries) and 15 weight parts ofsqualane (Wako Pure Chemical Industries) were supplied to adissolver-type high-speed mixer and homogeneously blended to give amixed solution.

The thus-obtained mixed solution was applied to a silicone-treatedpolyethylene terephthalate film (38 μm thick) and then dried at 60° C.for 30 minutes to give a 80-μm-thick adhesive layer.

The above adhesive layer was then transferred onto the ethylene-vinylacetate copolymer layer of a 34 μm thick polyethyleneterephthalate/ethylene-vinyl acetate copolymer laminate film, to give atape-form preparation.

EXAMPLE 148

[Synthesis of acrylic adhesive]

The procedure of Example 147 was followed to give an adhesive solutionwith a solid content of 50% by weight.

[Production of tape-form preparation]

A tape-form preparation was obtained in the same manner as in Example147 except that 139.98 weight parts of the above adhesive solution, 0.01weight part of prednisolone (Wako Pure Chemical Industries), 15 weightparts of vitamin E acetate (Wako Pure Chemical Industries) and 15 weightparts of squalane (Wako Pure Chemical Industries) were used.

EXAMPLE 149

[Synthesis of acrylic adhesive]

The procedure of Example 147 was followed to give an adhesive solutionwith a solid content of 50% by weight.

[Production of tape-form preparation]

A tape-form preparation was obtained in the same manner as in Example147 except that 166.99 weight parts of the above adhesive solution,0.005 weight part of dexamethasone (Wako Pure Chemical Industries), 1.5weight parts of vitamin E acetate (Wako Pure Chemical Industries) and 15weight parts of squalane (Wako Pure Chemical Industries) were used.

EXAMPLES 150 TO 167 AND COMPARATIVE EXAMPLES 21 TO 24

Ointments were prepared by supplying Plastibase (Taisho Pharmaceutical),bufexamac (Sigma), indomethacin (Sigma), vitamin E acetate (Wako PureChemical Industries), squalane (Wako Pure Chemical Industries), squalene(Sigma), isopropyl myristate (Nacalai Tesque), dexamethasone (Wako PureChemical Industries) and prednisolone (Wako Pure Chemical Industries),in amounts specified below in Table 15, to a mortar, and kneading themortar contents until the components other than Plastibase weredissolved in the latter.

TABLE 15 Composition (weight %) Isopropyl Plastibase BufexamacIndomethacin Vitamin E Squalane Squalene myristate DexamethasonePrednisolone Example 150 79.5 5 — 0.5 15 — — — — 151 60 5 — 20 15 — — —— 152 45 5 — 20 30 — — — — 153 30 5 — 50 15 — — — — 154 15 5 — 50 30 — —— — 155 69.5 5 — 0.5 15 — 10 — — 156 50 5 — 20 15 — 10 — — 157 35 5 — 2030 — 10 — — 158 64 — 1 20 15 — — — — 159 54 — 1 20 15 — 10 — — 160 70 5— 20 — 5 — — — 161 45 5 — 20 — 30 — — — 162 55 5 — 20 15 5 — — — 163 155 — 20 30 30 — — — 164 74 — 1 20 — 5 — — — 165 49 — 1 20 — 30 — — — 16659 — 1 20 15 5 — — — 167 19 — 1 20 30 30 — — — Comparative 21 95 5 — — —— — — — Example 22 99 — 1 — — — — — — 23 99.9 — — — — — — 0.1 — 24 99.5— — — — — — — 0.5

The thus-obtained ointments were tested as in Test Examples 1 to 4, 7and 9 to 11. In Test Examples 1 to 4, 7, 10 and 1, each ointment wastested using 5 rats and the results were expressed in terms of meanvalue. In Test Example 9, each ointment was tested using 5 guinea pigsand the results were expressed in terms of mean value. The results thusobtained are shown in Table 16.

TABLE 16 Test Example 10 1 2 3 4 7 9 (g/ 11 (%) (%) (%) (g) (%) (%) cm)(%) Example 150 21.6 18.2 24.6 2 — — — 10.1 151 83.8 29.4 84.1 1 19.366.4 261 23.7 152 86.9 32.8 87.9 3 — — — 27.5 153 83.8 33.3 87.9 0 — — —31.2 154 84.8 37.3 88.1 1 — — — 32.5 155 26.1 23.3 24.5 2 — — — 20.8 15687.8 44.9 91.2 1 21.1 75.4 271 31.9 157 89.8 46.3 86.6 1 — — — 36.2 15881.4 27.8 78.6 0 14.8 68.1 233 31.9 159 80.2 39.8 86.2 2 — — — 32.5 16084.0 30.1 85.6 1 — — — 24.8 162 87.2 31.9 88.1 2 — — — 27.3 164 83.529.6 84.8 1 — — — 30.1 166 86.8 31.8 88.2 2 — — — 36.9 ComparativeExample 21 2.1 3.2 4.6 2 1.9 40.2 187  3.8 22 1.8 1.2 2.8 1 3.8 50.8 18010.8 23 43.2 38.6 54.3 −6 40.2 — — 53.6 24 42.8 36.2 52.6 −4 38.5 — —49.2 Control — — — 0 — — 175 —

The results shown in Table 16 indicate that the external preparation forthe treatment of dermatoses according to the third aspect of the presentinvention are comparable or superior in effect to the conventional,nonsteroidal antiinflammatory agent-containing preparations.Furthermore, the external preparations according to the third aspect ofthe invention did not show any significant body weight loss due to sideeffects, unlike the conventional adrenocortical hormone-containingpreparations. It was thus proved that the present invention, in itsthird aspect, provides highly safe external preparations for thetreatment of dermatoses, which are widely effective against dermatoses.

EXAMPLES 168 TO 199

Ointments were prepared by supplying white petrolatum (MaruishiPharmaceutical), bufexamac (Sigma), indomethacin (Sigma), vitamin Eacetate (Wako Pure Chemical Industries), squalane (Wako Pure ChemicalIndustries), squalene (Sigma), N-lauroylsarcosine (Nacalai Tesque),fumaric acid (Nacalai Tesque), cetyl lactate (Van-Dyk) and isopropylmyristate (Nacalai Tesque), in amounts specified below in Tables 17 and18, to a mortar, and kneading the mortar contents until the componentsother than white petrolatum were dissolved in the latter.

TABLE 17 Composition (weight %) White Lauroyl- Fumaric Cetyl Isopropylpetrolatum Bufexamac Indomethacin Vitamin E Squalane sarcosine acidlactate myristate Example 168 78.5 5 — 0.5 15 1 — — — 169 59.0 5 — 20 151 — — — 170 29.0 5 — 50 15 1 — — — 171 78.5 5 — 0.5 15 — 1 — — 172 59.05 — 50 15 — 1 — — 173 29.0 5 — 50 15 — 1 — — 174 78.5 5 — 0.5 15 — — 1 —175 59.0 5 — 20 15 — — 1 — 176 29.0 5 — 50 15 — — 1 — 177 69.5 5 — 0.515 — — — 10 178 50.0 5 — 20 15 — — — 10 179 20.0 5 — 50 15 — — — 10 18082.5 — 1 0.5 15 1 — — — 181 63.0 — 1 20 15 1 — — — 182 33.0 — 1 50 15 1— — — 183 82.5 — 1 0.5 15 — 1 — — 184 63.0 — 1 20 15 — 1 — — 185 33.0 —1 50 15 — 1 — — 186 82.5 — 1 0.5 15 — — 1 — 187 63.0 — 1 20 15 — — 1 —188 33.0 — 1 50 15 — — 1 — 189 73.5 — 1 0.5 15 — — — 10 190 54.0 — 1 2015 — — — 10 191 24.0 — 1 50 15 — — — 10

TABLE 18 Composition (weight %) White Indo- petro- Bufex- meth- Vitaminlatum amac acin E Squalane Squalene Example 192 70.0 5 — 20 — 5 193 45.05 — 20 — 30 194 55.0 5 — 20 15 5 195 15.0 5 — 20 30 30 196 74.0 — 1 20 —5 197 49.0 — 1 20 — 30 198 59.0 — 1 20 15 5 199 19.0 — 1 20 30 30

EXAMPLES 200 TO 213

Liniments were prepared by supplying olive oil (MaruishiPharmaceutical), bufexamac (Sigma), indomethacin (Sigma), vitamin Eacetate (Wako Pure Chemical Industries), squalane (Wako Pure ChemicalIndustries) and squalene (Sigma), in amounts specified below in Table19, to a beaker, and stirring the beaker contents until the whole becamehomogeneous.

TABLE 19 Composition (weight %) Olive Bufex- Indo- Vitamin oil amacmethacin E Squalane Squalene Example 200 79.5 5 — 0.5 15 — 201 60.0 5 —20 15 — 202 30.0 5 — 50 15 — 203 83.5 — 1 0.5 15 — 204 64.0 — 1 20 15 —205 34.0 — 1 50 15 — 206 70.0 5 — 20 — 5 207 45.0 5 — 20 — 30 208 55.0 5— 20 15 5 209 15.0 5 — 20 30 30 210 74.0 — 1 20 — 5 211 49.0 — 1 20 — 30212 59.0 — 1 20 15 5 213 19.0 — 1 20 30 30

EXAMPLE 214

[Synthesis of acrylic adhesive]

A separable flask equipped with a stirrer and a condenser was chargedwith 301.1 weight parts of 2-ethylhexyl methacrylate, 34.9 weight partsof 2-ethylhexyl acrylate, 48.3 weight parts of dodecyl methacrylate,0.0384 weight part of 1,6-hexaneglycol dimethacrylate and 256.0 weightparts of ethyl acetate, and the flask contents were heated to 70° C.with stirring and nitrogen substitution.

A solution of 2.0 weight parts of lauroyl peroxide in 10.0 weight partsof cyclohexane was divided into 10 aliquots. One aliquot was added tothe separable flask to thereby initiate the polymerization. Starting at5 hours after initiation of the polymerization, the remaining 9 aliquotswere added one by one at 1-hour intervals. After completion of theaddition, the reaction was further carried out for 19 hours. Forviscosity adjustment, five 27 weight part portions of ethyl acetate wereadded one by one at 5-hour intervals after initiation of the reaction.

After completion of the reaction, the reaction mixture was cooled andethyl acetate was further added to give an adhesive solution with asolid content of 50% by weight.

[Production of tape-form preparation]

The above adhesive solution (120 weight parts), 5 weight parts ofbufexamac, 20 weight parts of vitamin E acetate (Wako Pure ChemicalIndustries) and 15 weight parts of squalane (Wako Pure ChemicalIndustries) were supplied to a dissolver-type high-speed mixer andhomogeneously blended to give a mixed solution.

The thus-obtained mixed solution was applied to a silicone-treatedpolyethylene terephthalate film (38 μm thick) and then dried at 60° C.for 30 minutes to give a 80-μm-thick adhesive layer.

The above adhesive layer was then transferred onto the ethylene-vinylacetate copolymer layer of a 34 μm thick polyethyleneterephthalate/ethylene-vinyl acetate copolymer laminate film, to give atape-form preparation.

EXAMPLE 215

A tape-form preparation was obtained in the same manner as in Example214 except that 15 weight parts of squalene (Sigma) was used in lieu of15 weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLE 216

A tape-form preparation was obtained in the same manner as in Example214 except that 15 weight parts of squalane (Wako Pure ChemicalIndustries) plus 15 weight parts of squalene (Sigma) was used in lieu of15 weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLE 217

[Synthesis of acrylic adhesive]

The procedure of Example 214 was followed to give an adhesive solutionwith a solid content of 50% by weight.

[Production of tape-form preparation]

A tape-form preparation was produced in the same manner as in Example214, using 120 weight parts of the above adhesive solution, 5 weightparts of bufexamac, 10 weight parts of vitamin E acetate (Wako PureChemical Industries), 15 weight parts of squalane (Wako Pure ChemicalIndustries) and 10 weight parts of isopropyl myristate.

EXAMPLE 218

A tape-form preparation was produced in the same manner as in Example217 except that 15 weight parts of squalene (Sigma) was used in lieu of15 weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLE 219

A tape-form preparation was produced in the same manner as in Example217 except that 15 weight parts of squalane (Wako Pure ChemicalIndustries) plus 15 parts of squalene (Sigma) was used in lieu of 15weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLES 220 TO 231 AND COMPARATIVE EXAMPLES 25 TO 27

Ointments were prepared by supplying Plastibase (Taisho Pharmaceutical),diphenhydramine (Kongo Chemical), vitamin E acetate (Wako Pure ChemicalIndustries), squalane (Wako Pure Chemical Industries), squalene (Sigma),isopropyl myristate (Nacalai Tesque), dexamethasone (Wako Pure ChemicalIndustries) and prednisolone (Wako Pure Chemical Industries), in amountsspecified below in Table 20, to a mortar, and kneading the mortarcontents until the components other than Plastibase were dissolved inthe latter.

In Table 20 as well as in Table 22 (to be given later herein), IPMstands for isopropyl myristate, and DH for diphenhydramine.

TABLE 20 Composition (weight %) Plastibase DH Vitamin E SqualaneSqualene IPM Dexamethasone Prednisolone Example 220 83.5 1 0.5 15 — — —— 221 64 1 20 15 — — — — 222 49 1 20 30 — — — — 223 34 1 50 15 — — — —224 19 1 50 30 — — — — 225 73.5 1 0.5 15 — 10 — — 226 54 1 20 15 — 10 —— 227 39 1 20 30 — 10 — — 228 73 2 20 — 5 — — — 229 48 2 20 — 30 — — —230 58 2 20 15 5 — — — 231 18 2 20 30 30 — — — Comparative 25 99 1 — — —— — — Example 26 99.9 — — — — — 0.1 — 27 99.5 — — — — — — 0.5

The thus-obtained ointments were tested as in Test Examples 1, 4, 7 and9 to 11. In Test Examples 1 to 4, 7, 10 and 11, each ointment was testedusing 5 rats and the results expressed in terms of mean value. In TestExample 9, each ointment was tested using 5 guinea pigs and the resultswere expressed in terms of mean value. The results thus obtained areshown in Table 21.

TABLE 21 Test Example 1 2 3 4 7 9 10 11 (%) (%) (%) (g) (%) (%) (g/cm)(%) Example 220 20.1 53.3 23.9 2 — — — 10.1 221 81.2 74.8 84.1 1 18.729.6 228 24.7 222 84.6 75.2 82.6 3 — — — 28.1 222 87.3 78.8 87.7 0 — — —31.8 224 88.8 80.3 89.9 1 — — — 32.7 225 25.7 64.6 30.3 2 — — — 14.4 22685.5 77.5 88.8 1 30.1 35.4 240 29.6 227 87.8 77.8 88.9 1 — — — 30.3 22882.9 81.4 84.8 1 — — — 25.8 229 88.3 85.5 87.2 2 — — — 30.2 230 89.186.3 88.1 1 — — — 31.1 231 90.1 89.3 89.9 2 — — — 33.0 ComparativeExample  25 3.9 51.3 4.1 2 6.2 5.7 182 2.6  26 43.2 38.6 54.3 −6 40.2 —— 53.6  27 42.8 36.2 52.6 −4 38.5 — — 49.2 Control — — — 0 — — 175 —

The results shown in Table 21 indicate that the external preparation forthe treatment of dermatoses according to the fourth aspect of thepresent invention are comparable or superior in effect to theconventional, antihistaminic agent-containing preparations. Furthermore,the external preparations according to the fourth aspect of theinvention did not show any significant body weight loss due to sideeffects, unlike the conventional adrenocortical hormone-containingpreparations. It was thus proved that the present invention, in itsfourth aspect, provides highly safe external preparations for thetreatment of dermatoses, which are widely effective against dermatoses.

EXAMPLES 232 TO 247

Ointments were prepared by supplying white petrolatum (MaruishiPharmaceutical), diphenhydramine (Kongo Chemcial), vitamin E acetate(Wako Pure Chemical Industries), squalane (Wako Pure ChemicalIndustries), squalene (Sigma), N-lauroylsarcosine (Nacalai Tesque),fumaric acid (Nacalai Tesque), cetyl lactate (Van Dyk) and isopropylmyristate (Nacalai Tesque), in amounts specified below in Table 22, to amortar, and kneading the mortar contents until the components other thanwhite petrolatum were dissolved in the latter.

In Table 22, LS stands for N-lauroylsarcosine.

TABLE 22 Composition (weight %) White Fumaric Cetyl petrolatum DHVitamin E Squalane Squalene LS acid lactate IPM Example 232 82.5 1 0.515 — 1 — — — 233 63.0 1 20 15 — 1 — — — 224 33.0 1 50 15 — 1 — — — 23582.5 1 0.5 15 — — 1 — — 236 63.0 1 20 15 — — 1 — — 237 33.0 1 50 15 — —1 — — 238 82.5 1 0.5 15 — — — 1 — 239 63.0 1 20 15 — — — 1 — 240 33.0 150 15 — — — 1 — 241 73.5 1 0.5 15 — — — — 10 242 54.0 1 20 15 — — — — 10243 24.0 1 50 15 — — — — 10 244 73.0 2 20 — 5 — — — — 245 48.0 2 20 — 30— — — — 246 58.0 2 20 15 5 — — — — 247 18.0 2 20 30 30 — — — —

EXAMPLES 248 TO 254

Liniments were prepared by feeding olive oil (Maruishi Pharmaceutical),diphenhydramine (Kongo Chemical), vitamin E acetate (Wako ChemicalIndustries), squalane (Wako Pure Chemical Industries) and squalene(Sigma), in amounts specified below in Table 23, to a beaker, andstirring the beaker contents until the whole became homogeneous.

TABLE 23 Composition (weight %) Diphen- Olive hydra- Vita- Squa- Squa-oil mine min E lane lene Example 248 83.5 1 0.5 15 — 249 64.0 1 20 15 —250 34.0 1 50 15 — 251 73.0 2 20 —  5 252 48.0 2 20 — 30 253 58.0 2 2015  5 254 18.0 2 20 30 30

EXAMPLE 255

[Synthesis of acrylic adhesive]

A separable flask equipped with a stirrer and a condenser was chargedwith 301.1 weight parts of 2-ethylhexyl methacrylate, 34.9 weight partsof 2-ethylhexyl acrylate, 48.3 weight parts of dodecyl methacrylate,0.0384 weight part of 1,6-hexaneglycol dimethacrylate and 256.0 weightparts of ethyl acetate, and the flask contents were heated to 70° C.with stirring and nitrogen substitution.

A solution of 2.0 weight parts of lauroyl peroxide in 10.0 weight partsof cyclohexane was divided into 10 aliquots. One aliquot was added tothe separable flask to thereby initiate the polymerization. Starting at5 hours after initiation of the polymerization, the remaining 9 aliquotswere added portion by portion at 1-hour intervals. After completion ofthe addition, the reaction was further carried out for 19 hours. Forviscosity adjustment, five 27 weight part portions of ethyl acetate wereadded portion by portion at 5-hour intervals after initiation of thereaction.

After completion of the reaction, the reaction mixture was cooled andethyl acetate was further added to give an adhesive solution with asolid content of 50% by weight.

[Production of tape-form preparation]

The above adhesive solution (128 weight parts), 1 weight parts ofdiphenhydramine, 20 weight parts of vitamin E acetate (Wako PureChemical Industries) and 15 weight parts of squalane (Wako Pure ChemicalIndustries) were fed to a dissolver-type high-speed mixer andhomogeneously blended to give a mixed solution.

The thus-obtained mixed solution was applied to a silicone-treatedpolyethylene terephthalate film (38 μm thick) and then dried at 60° C.for 30 minutes to give a 80-μm-thick adhesive layer.

The above adhesive layer was then transferred onto the ethylene-vinylacetate copolymer layer of a 34 μm thick polyethyleneterephthalate/ethylene-vinyl acetate copolymer laminate film, to give atape-form preparation.

EXAMPLE 256

A tape-form preparation was obtained in the same manner as in Example255 except that 15 weight parts of squalene (Sigma) was used in lieu of15 weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLE 257

A tape-form preparation was obtained in the same manner as in Example255 except that 15 weight parts of squalane (Wako Pure ChemicalIndustries) plus 15 weight parts of squalene (Sigma) was used in lieu of15 weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLE 258

[Synthesis of acrylic adhesive]

The procedure of Example 255 was followed to give an adhesive solutionwith a solid content of 50%.

[Production of tape-form preparation]

A tape-form preparation was obtained in the same manner as in Example255, using 128 weight parts of the above adhesive solution, 1 weightpart of diphenhydramine, 10 weight parts of vitamin E acetate (Wako PureChemical Industries), 15 weight parts of squalane (Wako Pure ChemicalIndustries) and 10 weight parts of isopropyl myristate.

EXAMPLE 259

A tape-form preparation was obtained in the same manner as in Example258 except that 15 weight parts of squalene (Sigma) was used in lieu of15 weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLE 260

A tape-form preparation was obtained in the same manner as in Example258 except that 15 weight parts of squalane (Wako Pure ChemicalIndustries) plus 15 parts of squalene (Sigma) was used in lieu of 15weight parts of squalane (Wako Pure Chemical Industries).

EXAMPLES 261 TO 278 AND COMPARATIVE EXAMPLES 28 TO 41

Ointments were prepared by feeding Plastibase (Taisho Pharmaceutical),vitamin E acetate (Wako Pure Chemical Industries), squalene (Sigma),squalane (Wako Pure Chemical Industries), isopropyl myristate (NacalaiTesque), dexamethasone (Wako Pure Chemical Industries) and prednisolone(Wako Pure Chemical Industries), in amounts (parts by weight) specifiedbelow in Tables 24 and 25, to a mortar, and kneading the mortar contentsuntil the components other than Plastibase were dissolved in the latter.

In Tables 24 and 25 as well as in Tables 30 and 32 (to be given laterherein), VE stands for vitamin E acetate, SQE for squalene, SQA forsqualane, IPM for isopropyl myristate, Dx for dexamethasone, and Pr forprednisolone.

TABLE 24 Composition (weight %) Plasti- base VE SQE SQA IPM Example 26181.5  2 1.5 15 — 262 78.5  5 1.5 15 — 263 87.0 10 1.5 1.5 — 264 73.5 101.5 15 — 265 58.5 10 1.5 30 — 266 43.5 10 1.5 45 — 267 60.0 10 15 15 —268 45.0 10 15 30 — 269 30.0 10 15 45 — 270 45.0 10 30 15 — 271 63.5 201.5 15 — 272 50.0 20 15 15 — 273 35.0 20 15 30 — 274 43.5 40 1.5 15 —275 23.5 60 1.5 15 — 276 71.5  2 1.5 15 10 277 63.5 10 1.5 15 10 27853.5 20 1.5 15 10

TABLE 25 Composition (weight %) Plastibase VE SQE IPM Dx Pr Comparative28 96.5 2 1.5 — — — Example 29 93.5 5 1.5 — — — 30 88.5 10 1.5 — — — 3175.0 10 15 — — — 32 60.0 10 30 — — — 33 78.5 20 1.5 — — — 34 65.0 20 15— — — 35 58.5 40 1.5 — — — 36 38.5 60 1.5 — — — 37 86.5 2 1.5 10 — — 3878.5 10 1.5 10 — — 39 68.5 20 1.5 10 — — 40 99.9 — — — 0.1 — 41 99.5 — —— — 0.5

The thus-obtained ointments were tested as in Test Examples 1 to 5, 7and 11 and further tested according to the methods mentioned below inTest Examples 12 to 14. In Test Examples 1 to 4, 7, 11, 12 and 14, eachointment was tested using 5 rats and the results were expressed in termsof mean value. In Test Example 13, each ointment was tested using 5guinea pigs and the results were expressed in terms of mean value. Theresults thus obtained are shown in Tables 26 to 29.

TEST EXAMPLE 12 Effect on Type II Allergic Reaction

(1) Preparation of Rabbit Anti-rat Serum

Rabbit anti-rat serum was prepared by the method of Eda et al. (FoliaPharmacologica Japonica; 66, 237, 1970).

Thus, serum was collected from male Wistar rats weighing 150 to 200 g.An equivolume mixture (emulsion) of this rat serum and Freund's completeadjuvant (Difco) was used as an antigen preparation and 0.5 ml thereofwas injected into the right and left gluteal muscles of each male rabbit(New Zealand white strain) four times at one-week intervals. Seven daysafter the last injection, blood was collected from the carotid arteryand serum was separated and recovered. Thus, rabbit anti-rat serum wasobtained.

(2) Effect on Anti-rat Serum-induced Intradermal Reaction

The ointments were examined for effect on anti-rat serum-inducedintracutaneous reaction by the method of Kuriyama et al. (FoliaPharmacologica Japonica; 95, 83, 1990).

The above rabbit anti-rat serum was 4-fold diluted with physiologicalsaline and 0.1 ml of the dilution was intradermally injected into theback of each male Wistar rat weighing about 200 g. Then, 0.1 g of eachof the ointments obtained in the above-mentioned examples andcomparative examples was applied to the rat skin at the site ofapplication of the anti-rat serum in the same manner as in Test Example1.

Further, 2 hours thereafter, 0.5% Evans' blue solution in physiologicalsaline was intravenously administered at a dose of 2.5 ml/kg.

The dye that had leaked out at the site of the thus-induced reaction wasextracted and assayed by the method of Harada et al. (Journal ofPharmaceutics Pharmacology; 23, 218, 1971).

Thus, 30 minutes after Evans' blue administration, the animals weresacrificed. The skin containing the dye that had leaked out was excisedfrom the reaction area, minced and immersed in a mixed solution composedof 0.3% aqueous solution of sodium sulfate and acetone (3:7, v/v) for atleast 48 hours for effecting extraction of the dye that had leaked out.The dye thus extracted was then assayed by absorbance at 620 nm.

As a control, the ointment base (Plastibase) alone was applied in lieuof the test preparation. Thereafter, the same procedure was followed andthe dye extracted was assayed by absorbance.

From the results of determination of the amount (O) of the dye extractedfrom the site of application of the control and of the amount (P) of thedye extracted from the site of application of each test preparation, thedye-leakage inhibition percentage was calculated as follows:

Dye-leakage inhibition (%)=[(O−P)/O]×100

The results thus obtained are shown in Tables 28 and 29.

TEST EXAMPLE 13 Effect on Solar Dermatitis (ultraviolet erythema)

The ointments were examined for effect on ultraviolet-induced erythemaby the method of Tsuji et al. (Oyo Yakuri; 23, 567, 1982). Thus, theback of guinea pigs weighing 250 to 300 g was clipped of hairs. The skinof the back was covered with a light-shielding cloth having three roundholes with a diameter of 7 mm and ultraviolet irradiation was carriedout from a distance of 20 cm for 30 seconds using a 1,000 wattultraviolet lamp (Toshiba). Immediately thereafter, 0.1 g of each of theointments obtained in the above-mentioned examples and comparativeexamples was applied as the test preparation to the site ofultraviolet-induced erythema in the same manner as in Test Example 1.

After 24 hours, the skin reactions were scored according to the criteriashown below and the sum of scores for the three sites was used forevaluating each test preparation.

As a control, the ointment base (Plastibase) alone was applied in thesame manner in lieu of the test preparation and thereafter the skinreactions were evaluated by the same procedure.

Evaluation Criteria

0: No change

1: Slight erythema

2: Medium erythema

3: Marked erythema

4: Marked erythema and edema

From the erythema score (M) for the control and the erythema score (N)for the test preparation application sites, the ultraviolet-inducederythema healing percentage was calculated as follows:

UV-induced erythema healing (%)=[(M−N)/M]×100

The results thus obtained are shown in Table 28 and 29.

TEST EXAMPLE 14 Effect on Wound Healing

The ointments were evaluated for effect on wound healing by the methodof Sakyo et al. (Oyo Yakuri; 43, 121, 1992). The back of 5-week-oldWistar rats was shaved of hairs and using a surgical knife, a 30 mm-longincision was made along the median line under ether anesthesia.Immediately after incision, the wound was sutured in 3 equispacedpositions.

Then, 0.2 g samples from the ointments obtained in the above examplesand comparative examples were respectively spread on gauze (3-ply), 2.5cm×5 cm, and applied against the wounded area and an occulusive dressingusing a stretchable bandage was applied for fixation. Theointment-coated gauze was exchanged once/daily.

The suture was removed 3 days after commencement of the experiment. Onday 8, the skin covering the whole wounded area was excised from eachrat and 1 cm-wide skin strips parallel to the wound line (2 strips/rat)were prepared. Both ends of each strip were fixed to an NRM-3002D-Lrheometer (FUDOH) and the tension force (g/cm) required for cutting thestrip at the wound site was measured. The mean measured value for twostrips was taken as the tension value for one sample.

As a control, the ointment base (Plastibase) alone was applied in thesame manner in lieu of the test preparation and thereafter tensionmeasurements were carried out following the same procedure.

From the tensile strength (Q) of the healed wound in the control groupand the tensile strength (R) of the healed wound for the testpreparation application sites, the wound healing percentage wascalculated as follows:

Wound healing (%)=[(Q−R)/Q]×100

The results are shown in Table 28 and 29.

TABLE 26 Test Example 1 2 3 4 (%) (%) (%) (g) Example 261 25.0 20.9 31.10 262 30.9 24.1 37.0 1 263 30.3 23.9 36.6 1 264 40.5 34.9 43.7 2 26545.8 41.9 49.7 2 266 56.0 48.5 59.1 2 267 54.7 47.4 59.4 2 268 61.3 56.767.3 2 269 64.1 60.3 74.9 3 270 77.0 72.4 89.9 3 271 52.2 44.6 55.3 2272 70.1 59.9 74.3 2 273 80.3 72.1 84.6 3 274 67.3 58.9 67.6 2 275 71.762.4 70.7 3 276 36.2 27.1 45.6 2 277 52.9 40.1 57.0 2 278 73.2 67.2 81.52

TABLE 27 Test Example 1 2 3 4 (%) (%) (%) (g) Comparative 28 19.2 14.924.3 −1  Example 29 23.8 17.2 28.9 −1  30 27.2 21.3 30.1 0 31 31.2 25.134.4 1 32 35.2 29.7 38.9 1 33 38.6 33.0 41.0 1 34 45.3 38.4 46.7 0 3549.9 43.6 50.1 2 36 53.1 46.2 52.4 2 37 26.8 20.1 33.8 0 38 39.2 29.742.2 1 39 53.1 45.2 58.1 2 40 51.4 43.2 54.8 −13  41 52.0 42.1 54.9 −12 Control — — — 0

TABLE 28 Test Examples 7 11 12 13 14 5 (%) (%) (%) (%) (%) Example 261 2— 15.7 — 5.3 — 262 2 — 21.1 — — — 263 2 — 20.7 — — — 264 2 24.2 26.224.1 10.1 19.1 265 2 — 30.9 — — — 266 1 — 36.1 — — — 267 2 33.8 35.333.9 16.1 27.1 268 1 — 41.9 — — — 269 0 — 45.1 — — — 270 1 — 54.1 — 21.3— 271 2 32.9 35.3 33.1 15.6 26.5 272 2 — 44.2 — 19.8 — 273 0 — 53.1 — —— 274 1 — 46.6 — — — 275 0 — 49.8 — — — 276 2 — 23.1 — 10.1 — 277 2 33.833.9 33.5 16.5 28.1 278 2 70.3 56.2 71.2 22.4 64.3

TABLE 29 Test Examples 7 11 12 13 14 5 (%) (%) (%) (%) (%) Comparative28 2 — 12.1 — 2.1 — Example 29 2 — 16.2 — — — 30 2 13.2 17.6 14.1 5.910.0 31 2 — 20.1 — — — 32 2 — 23.9 — — — 33 2 21.8 26.2 22.1 8.2 16.8 342 — 31.2 — — — 35 2 — 34.5 — — — 36 0 — 36.9 — — — 37 2 — 17.1 — 5.4 —38 2 22.5 25.1 23.1 8.6 17.2 39 2 33.0 41.2 34.1 11.3 28.1 40 2 — 40.3 —8.2 — 41 2 — 39.7 — 5.4 — Control — — — — — —

EXAMPLES 279 TO 288 AND COMPARATIVE EXAMPLES 42 TO 56

Ointments were prepared by feeding white petrolatum (MaruishiPharmaceutical), vitamin E acetate (Wako Pure Chemical Industries),squalene (Sigma), squalane (Wako Pure Chemical Industries),N-lauroylsarcosine (Nacalai Tesque), fumaric acid (Nacalai Tesque),cetyl lactate (Van-Dyk) and isopropyl myristate (Nacalai Tesque), inamounts (parts by weight) specified below in Table 30, to a mortar, andkneading the mortar contents until the components other than whitepetrolatum were dissolved in the latter.

In Table 30, LS stands for N-lauroylsarcosine.

TABLE 30 Composition (weight %) Cetyl White Fumaric lac- petrolatum VESQE SQA LS acid tate IPM Example 279 62.5 20 1.5 15 1 — — — 280 49 20 1515 1 — — — 281 62.5 20 1.5 15 — 1 — — 282 49 20 15 15 — 1 — — 283 62.520 1.5 15 — — 1 — 284 49 20 15 15 — — 1 — 285 53.5 20 1.5 15 — — — 10286 40 20 15 15 — — — 10 287 63.5 20 1.5 15 — — — — 288 50 20 15 15 — —— — Comparative Example  42 77.5 20 1.5 — 1 — — —  43 64 20 15 — 1 — — — 44 44 40 15 — 1 — — —  45 77.5 20 1.5 — — 1 — —  46 64 20 15 — — 1 — — 47 44 40 15 — — 1 — —  48 77.5 20 1.5 — — — 1 —  49 64 20 15 — — — 1 — 50 44 40 15 — — — 1 —  51 68.5 20 1.5 — — — — 10  52 55 20 15 — — — —10  53 35 40 15 — — — — 10  54 78.5 20 1.5 — — — — —  55 65 20 15 — — —— —  56 45 40 15 — — — — —

The thus-obtained ointments were tested as in Test Examples 1 to 3 and11. The results obtained are shown in Table 31.

TABLE 31 Test Example 1 2 3 11 (%) (%) (%) (%) Example 279  72.1 66.478.9 56.1 280  — — — 61.3 281  71.2 66.0 78.5 55.9 282  — — — 60.3 283 73.1 66.8 79.8 56.3 284  — — — 61.9 285  72.2 66.9 80.7 56.1 286  — — —62.3 287  51.9 44.4 55.3 34.8 288  69.5 57.8 71.3 42.8 Comparative 4251.0 47.8 56.8 38.9 Example 43 — — — 41.2 44 — — — 47.3 45 52.1 45.854.6 39.1 46 — — — 41.5 47 47.3 48 52.8 45.2 57.6 39.8 49 — — — 42.1 50— — — 47.8 51 52.8 45.0 57.8 40.7 52 — — — 43.2 53 — — — 48.6 54 38.432.6 40.6 25.8 55 45.2 38.1 46.5 30.8 56 — — — 36.8

EXAMPLES 289 TO 292 AND COMPARATIVE EXAMPLES 57 AND 58

Liniments were prepared by feeding olive oil (Maruishi Pharmaceutical),vitamin E acetate (Wako Pure Chemical Industries), squalene (Sigma) andsqualane (Wako Pure Chemical Industries), in amounts (parts by weight)specified below in Table 32, to a beaker, and stirring the beakercontents until the whole became homogeneous.

The thus-obtained liniments were tested as in Test Examples 1 to 3 and11. The results obtained are shown in Table 32.

TABLE 32 External preparation composition (weight %) Test Example Olive1 2 3 11 oil VE SQE SQA (%) (%) (%) (%) Example 289 73.5 10 1.5 15 — — —27.5 290 60 10 15 15 — — — 36.2 291 63.5 20 1.5 15 52.3 45.9 55.6 35.1292 50 20 15 15 70.1 58.1 71.4 43.1 Comparative Example  57 75 10 15 — —— — 21.3  58 65 20 15 — 46.3 39.6 47.8 33.1

The results shown in Tables 26 to 29, 31 and 32 indicate that theexternal preparation for the treatment of dermatoses according to thefifth aspect of the present invention are comparable or superior ineffect to the vitamin E-squalene mixtures and the vitamin E-squalenemixtures supplemented with a transdermal absorption enhancer.Furthermore, when the external preparations according to the fifthaspect of the present invention were used, any significant body weightloss due to side effects was observed, unlike the case of theadrenocortical hormone-containing external preparations. It was thusshown that the present invention, in its fifth aspect, provides highlysafe external preparations for the treatment of dermatoses, which arewidely effective against dermatoses.

EXAMPLE 293

[Synthesis of acrylic adhesive]

A separable flask equipped with a stirrer and a condenser was chargedwith 301.1 weight parts of 2-ethylhexyl methacrylate, 34.9 weight partsof 2-ethylhexyl acrylate, 48.3 weight parts of dodecyl methacrylate,0.0384 weight part of 1,6-hexaneglycol dimethacrylate and 256.0 weightparts of ethyl acetate, and the flask contents were heated to 70° C.with stirring and nitrogen substitution.

A solution of 2.0 weight parts of lauroyl peroxide in 100.0 weight partsof cyclohexane was divided into 10 aliquots. One aliquot was added tothe separable flask to thereby initiate the polymerization. Starting at5 hours after initiation of the polymerization, the remaining 9 aliquotswere added one by one at 1-hour intervals. After completion of theaddition, the reaction was further carried out for 19 hours. Forviscosity adjustment, five 27 weight part portions of ethyl acetate wereadded portion by portion at 5-hour intervals after initiation of thereaction.

After completion of the reaction, the reaction mixture was cooled andethyl acetate was further added to give an adhesive solution with asolid content of 50% by weight.

[Production of tape-form preparation]

The above adhesive solution (100 weight parts), 20 weight parts ofvitamin E acetate (Wako Pure Chemical Industries), 15 weight parts ofsqualene (Sigma) and 15 weight parts of squalane (Wako Pure ChemicalIndustries) were fed to a dissolver-type high-speed mixer andhomogeneously blended to give a mixed solution.

The thus-obtained mixed solution was applied to a silicone-treatedpolyethylene terephthalate film (38 μm thick) and then dried at 60° C.for 30 minutes to give a 80-μm-thick adhesive layer.

The above adhesive layer was then transferred onto the ethylene-vinylacetate copolymer layer of a 34 μm thick polyethyleneterephthalate/ethylene-vinyl acetate copolymer laminate film, to give atape-form preparation.

EXAMPLE 294

[Synthesis of acrylic adhesive]

The procedure of Example 293 was followed to give an adhesive solutionwith a solid content of 50% by weight.

[Production of tape-form preparation]

A tape-form preparation was obtained in the same manner as in Example293, using 127 weight parts of the above adhesive solution, 10 weightparts of vitamin E acetate (Wako Pure Chemical Industries), 1.5 weightparts of squalene (Sigma), 15 weight parts of squalane (Wako PureChemical Industries) and 10 weight parts of isopropyl myristate.

INDUSTRIAL APPLICABILITY

Being constituted as detailedly described hereinabove, the externalpreparation for the treatment of dermatoses according to the firstaspect of the present invention shows high therapeutic effects againstdermatoses with reduced side effects as compared with externalpreparations whose main component is an adrenocortical hormone.Therefore, external preparations useful in the treatment of variousdermatoses can be obtained.

The external preparation for the treatment of dermatoses according tothe second aspect of the present invention contains vitamin E andsqualane in addition to an adrenocortical hormone and therefore shows ahigher therapeutic effect against intractable dermatoses as comparedwith the case where the adrenocortical hormone is used alone. Theaddition of vitamin E and squalane within respective specificconcentration ranges is more effective and makes it possible to obtainhigh therapeutic effects on dermatoses with low adrenocortical hormoneconcentrations. Therefore, external preparations for the treatment ofdermatoses which can be provided show high curative effects withreduction in side effects due to adrenocortical hormones. Furthermore,when said preparation further contains a specific transdermal absorptionenhancer, the active ingredients can readily be adsorbed into the skinand high therapeutic effects can be produced against intractabledermatoses.

The external preparation for the treatment of dermatoses according tothe third aspect of the present invention, which contains a nonsteroidalantiinflammatory agent, vitamin E and squalane and/or squalene, produceshigh therapeutic effects on intractable dermatoses with reduced sideeffects as compared with external preparations containing anadrenocortical hormone as a main active ingredient. Therefore, externalpreparations useful in various dermatoses can be obtained. Inparticular, when the nonsteroidal antiinflammatory agent, vitamin E andsqualane and/or squalene are used within respective specificconcentration ranges, external preparations useful in various dermatosescan be obtained more efficiently. Furthermore, when said preparationfurther contains a specific transdermal absorption enhancer, the activeingredients can readily be adsorbed into the skin and high therapeuticeffects can be produced even against intractable dermatoses, withreduced side effects as compared with external preparations containingan adrenocortical hormone as a main active ingredient. Thus, externalpreparations useful in the treatment of various dermatoses can beobtained.

The external preparation for the treatment of dermatoses according tothe fourth aspect of the present invention, which contains anantihistaminic agent, vitamin E and squalane and/or squalene, produceshigh therapeutic effects even on intractable dermatoses with reducedside effects as compared with external preparations containing anadrenocortical hormone as a main active ingredient. Therefore, externalpreparations useful in various dermatoses can be obtained. Inparticular, when the antihistaminic agent, vitamin E and squalane and/orsqualene are used within respective specific concentration ranges,external preparations useful in various dermatoses can be obtained moreefficiently. Furthermore, when said preparation further contains aspecific transdermal absorption enhancer, the active ingredients canreadily be adsorbed into the skin and high therapeutic effects can beproduced even against intractable dermatoses, with reduced side effectsas compared with external preparations containing an adrenocorticalhormone as a main active ingredient. Thus, external preparations usefulin the treatment of various dermatoses can be obtained.

The external preparation for the treatment of dermatoses according tothe fifth aspect of the present invention, which contains vitamin E,squalene and squalane, produces high therapeutic effects even onintractable dermatoses with reduced side effects as compared withexternal preparations containing an adrenocortical hormone as a mainactive ingredient. Therefore, external preparations useful in variousdermatoses can be obtained. When the preparation vitamin E, squalene andsqualane within respective specific concentration ranges, hightherapeutic effects can be produced even against intractable dermatoses,with reduced side effects as compared with external preparationscontaining an adrenocortical hormone as a main active ingredient.Therefore, external preparations useful in the treatment of variousdermatoses can be obtained. Furthermore, when said preparation furthercontains a specific transdermal absorption enhancer, the activeingredients can readily be adsorbed into the skin and high therapeuticeffects can be produced even against intractable dermatoses, withreduced side effects as compared with external preparations containingan adrenocortical hormone as a main active ingredient. Thus, externalpreparations useful in the treatment of various dermatoses can beobtained.

What is claimed is:
 1. An external preparation for the treatment ofdermatoses which consists essentially of vitamin E and squalane, as maincomponents, wherein the amount of vitamin E is about 20% by weight. 2.An external preparation for the treatment of dermatoses which consistsessentially of vitamin E and squalane, as main components, wherein theamount of vitamin E is at least 20% by weight.